Renin inhibiting compounds

ABSTRACT

Compounds which are amino acid derivatives and have the formula &lt;IMAGE&gt; I  in which R1 is hydrogen or methyl, R2 is ethyl, propyl or imidazol-4-yl, R3 is isobutyl, cyclohexylmethyl or benzyl, and A is defined as herein are useful as renin inhibitors.

This application is a continuation of application Ser. No. 07/254,003,filed Oct. 5, 1988, now abandoned.

SUMMARY OF THE INVENTION

The present invention comprises compounds which are amino acidderivatives and which have the formula ##STR2## is which R¹ is hydrogenor methyl, R² is ethyl, propyl or imidazol-4-yl, R³ is isobutyl.cyclohexylmethyl or benzyl, R⁴ is phenyl, furyl, vinyl, ethyl or1,2-dihydroxyethyl, and A is dibenzsuberaneacetic acid, 2 (2-pyridyl)benzoic acid, β-naphthylsuccinic acid monoethyl ester, 2-indolylaceticacid or dihydrocinnamic acid attached via the carboxyl group or A is oneof the following groups: ##STR3## in which the dotted line represents anadditional chemical bond, R⁵ is phenyl, naphthyl, indolyl, pyrazolyl,imidazolyl or pyridylmethyl, and R⁶ is hydrogen, alkyl, arylalkyl,alkoxycarbonyl- alkyl, alkylcarbonylalkyl, cycloalkylcarbonylalkyl,heterocycloalkylcarbonylalkyl, arylcarbonylalkyl, aminocarbonylalkyl,substituted aminocarbonylalkyl, aminocarbonyl, substitutedaminocarbonyl, alkoxycarbonyl, alkylcarbonyloxy, arylalkylcarbonyloxy,alkylaminocarbonyloxy, alkoxycarbonylamino, cyano or2,5-dimethylpyrrol-1-yl, with the proviso that R⁴ is notalkoxycarbonylamino when R³ is phenyl or α-naphthyl, Y is a bivalentresidue of optionally N- and/or α-methylated phenylglycine,cyclohexylglycine, phenylalanine, cyclohexylalanine, 4-fluorophenyl-alanine, 4-chlorophenylalanine, tyrosine, α-naphthylalanine,homophenylalanine, aspartic acid ethyl ester, glutamic acid t-butylester or gluramic acid benzyl ester linked with Z at the N-terminal, andZ is hydrogen, acyl or one of the following groups: ##STR4## thesecompounds being in the form of optically pure tereomers, diastereomermixtures, diastereomeric racemates or mixtures of diastereomericracemates, as well as pharmaceutically usable salts of such compounds.

These compounds are useful to control or prevent high blood pressure(hypertension) and cardiac insufficiency.

This invention also comprises a pharmaceutical composition containing acompound of formula I or pharmaceutically usable salt thereof as anactive ingredient and a method of treating or preventing high bloodpressure or cardiac insufficiency in a warm blooded animal by the use ofthe compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl" used in the present description. alone or incombination with other terms, means straight-chain and branched,saturated hydrocarbon residues with 1-8, preferably 1-4, carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec.-butyl, t-butyl, pentyl, hexyl and the like.

The term "alkoxy" means alkyl ether groups in which the term "alkyl" hasthe above meaning, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec.-butoxy, t-butoxy and the like. The term "cycloalkyl"means saturated, cyclic hydrocarbon residues with 3-8. preferably 3-6,carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

The term "heterocycloalkyl" refers in the same manner to saturated,3-8-membered, preferably 5- or 6-membered, cyclic hydrocarbon residuesin which one or two methylene groups are replaced by one or two oxygen,sulfur or optionally alkyl-, phenylalkyl-, alkanoyl- oralkanoyloxy-substituted nitrogen atoms, such as piperidinyl, pyrazinyl,N-benzyl-pyrazinyl, morpholinyl, N-methylpiperidinyl,N-benzyl-morpholinyl and the like.

The term "aryl" means a mono- or bicyclic aromatic hydrocarbon residuewith 6-14 carbon atoms which is optionally mono- or multi-substitutedwith alkyl, alkoxy, alkanoyloxy, amino, alkylamino, dialkylamino,alkanoylamino, hydroxy, halogen, trifluoromethyl or nitro, such asphenyl, α- or β-naphthyl, indenyl, anthryl or phenanthryl and the like.

The term "arylalkyl" means straight-chain or branched alkyl groups inwhich one or more hydrogen atoms are replaced by aryl groups, such asbenzyl, diphenylmethyl, trityl, α- or β-naphthylmethyl, 2-phenylethyl,3-phenyl -2-propyl, 4-phenyl-3-butyl, 2-(α- or β-naphthyl)ethyl,3-α-naphthyl-2-propyl, 4-a-naphthyl-3-butyl and the like, whereby thearomatic residue can in each case be mono- or multi-substituted asindicated above.

The term "substituted amino" means an amino group which is mono- ordi-substituted with alkyl, arylalkyl, alkanoyl, alkoxycarbonyl orarylalkoxycarbonyl, or disubstituted with C₃ -C₆ -alkylene which isoptionally interrupted by an oxygen, sulfur or alkyl-, phenylalkyl-,alkanoyl- or alkanoyloxy-substituted nitrogen atom.

The term "acyl" relates to the acyl group of a carboxylic acid, of ahalf ester of carbonic acid, of an optionally N-substituted carbamic orthiocarbamic acid, of an optionally N-substituted oxalamide, of asulfonic acid or of an optionally N-substituted amidosulfonic acid,especially those with the partial formulae R^(b) --CO--, R^(a)--O--CO--, (R^(b))(R^(b))N--CO--, (R^(b))(R^(b))N--CS--,(R^(b))(R^(b))N--CO--CO--, R^(b) --SO₂ --, or (R^(b))(R^(b))N--SO₂ -- inwhich R^(a) refers to an unsubstituted or substituted, saturated orunsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatichydrocarbon residue with up to 18, preferably 10, carbon atoms, anunsubstituted or substituted aromatic, heteroaromatic,aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon residue withup to 18, preferably 10, carbon atoms, or an unsubstituted orsubstituted, saturated 5- or 6-membered heterocycle, and R^(b) refers tohydrogen or has the same meaning as R^(a). The term "acyl" alsorepresents the monovalent residue of an amino acid, of a dipeptide or ofa tripeptide attached via the carboxyl group.

By way of illustration. R^(a) and R^(b) can be unsubstituted orsubstituted alkyl, alkenyl, alkynyl, mono-. bi- or tricycloalkyl,monocycloalkenyl, bicycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl orcycloalkenylalkyl. "Substituted alkyl" can be an alkyl residue in whichone or more hydrogen atoms can be substituted with hydroxy, alkoxy,aryloxy, alkanoyloxy, halogen, hydroxysulphonyloxy, carboxy,alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano,phosphono, esterified phosphono, amino or oxo, whereby the substituentsare present in the 1-position of the alkyl residue only when this isattached to the carbonyl group in the partial formula R^(b) --CO--.

Examples of substituted alkyl are 2-hydroxyethyl, methoxymethyl,2-methoxyethyl, phenoxymethyl, α- or β-naphthoxymethyl, acetoxymethyl,2-acetoxyethyl, chloromethyl, bromomethyl, 2-chloro- or 2-bromoethyl,hydroxysulphonyloxymethyl, 2-hydroxysulphonyloxyethyl, carboxy methyl,2-carboxyethyl, methoxycarbonylmethyl, 2-methoxy carbonylethyl,ethoxycarbonylmethyl, 2-ethoxycarbonyl, ethyl, carbamoylmethyl,2-carbamoylethyl, methylcarbamoyl methyl, dimethylcarbamoylmethyl,cyanomethyl, 2-cyanoethyl, 2-oxopropyl, 2-oxobutyl,hydroxycarboxymethyl, 1-hydroxy-2-carboxyethyl,hydroxyethoxycarbonylethyl, hydroxymethoxycarbonylethyl,acetoxymethoxycarbonylmethyl, 1,2-dihydroxy-2-carboxyethyl,1,2-dihydroxy-2-ethoxy-carbonylethyl,1,2-dihydroxy-2-methoxycarbonylethyl,1,2-diacetoxy-2-ethoxycarbonylethyl,1,2-diacetoxy-2-methoxycarbonylethyl, 1-α-naphthoxy-3-carboxypropyl,1-α-naphthoxy-2-ethoxycarbonylethyl,1-α-naopthoxy-3-t-butoxycarbonylpropyl,1-α-naphthoxy-2-benzyloxycarbonylethyl, 1-α-naphthoxy-3-carbamoylpropyl,α-naphthoxycyanomethyl, 1-α-naphthoxy-3-cyanopropyl,1-α-naphthoxy-4-dimethylaminobutyl and 1-α-naphthoxy-3-oxobutyl.

The term "alkenyl" refers to straight-chain or branched, unsaturatedhydrocarbon residues with 2-8, preferably 2-4, carbon atoms, whereby thedouble bond is present in the 1-position of the alkenyl residue onlywhen this is attached to the carbonyl group in the partial formula R^(b)--CO--. Examples of such alkenyl residues are vinyl, allyl, 2-butenyland 3-butenyl. The alkenyl residues can be substituted with the samesubstituents as the alkyl residues.

The term "alkynyl" refers to hydrocarbon residues with 2-8, preferably2-4, carbon atoms which contain a triple bond, such as ethynyl,1-propoynyl or 2-propynyl. The term "bicycloalkyl" refers to bicyclicsaturated hydrocarbon residues with 5-10, preferably 6-9, carbon atomssuch as bicyclo[3.1.0]hex-1-yl, bicyclo[3.1.0]hex-2- -yl,bicyclo[3.1.0]hex-3-yl, bicyclo[4.1.0]hept-1-yl,bicyclo[4.1.0]hept-4-yl, bicyclo[2.2.1]hept-2-yl,bicyclo[3.2.1]oct-2-yl, bicyclo[3.3.0]oct-3-yl, bicyclo[3.3.1}non-9-yl,α- or β-decahydronaphthyl and the like.

The term "tricycloalkyl" refers to a tricyclic saturated hydrocarbonresidue with 8-10 carbon atoms, such as 1-adamantyl.

The term "cycloalkenyl" refers to an unsaturated cyclic hydrocarbonresidue with 3-8, preferably 3-6, carbon atoms, such as 1-cyclohexenyl,1-4-cyclohexadienyl and the like.

The term "bicycloalkenyl" refers to a bicyclic unsaturated hydrocarbonresidue with 5-10, preferably 7-10, carbon atoms, such as5-norbornen-2-yl, bicyclo[2.2.2]octen-2-yl,hexahydro-4,7-methanoind-1-en-6 yl and the like.

Examples of cycloalkylalkyl are cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl and the like. Cyclohexylvinyl,cyclohexylallyl and the like are mentioned as examples ofcycloalkylalkenyl. Examples of cycloalkenylalkyl are1-cyclohexenylmethyl, 1,4-cyclohexadienylmethyl and the like.

The above-mentioned cycloaliphatic and cycloaliphaticaliphatic residuescan be substituted with the same substituents as those for alkyl.

An optionally substituted, aromatic or aromatic -aliphatic hydrocarbonresidue is, for example, unsubstituted or substituted aryl, arylalkyl orarylalkenyl. Styryl, 3-phenylallyl, 2-(α-naphthyl)vinyl,2-(β-naphthyl)vinyl and the like are examples of arylalkenyl.

In the heteroaromatic or heteroaromatic-aliphatic hydrocarbon residue,the heterocycle is mono-, bi- or tricyclic and contains one to twonitrogen atoms and/or one oxygen or sulfur atom and is linked with thegroup --CO--, --O--CO--, >N--CO--, >N--CS--, >N--CO--CO, --SO₂ or>N--SO₂ -- through one of its ring carbon atoms. Examples of suchheteroaromatic hydrocarbon residues are pyrrolyl, furyl, thienyl,imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinylor a benz-fused, cyclopenta-, cyclohexa- or cyclopenta-fused derivativeof these residues. The heteroaromatic residue can be substituted on anitrogen atom with alkyl, phenyl or phenylalkyl, for example, benzyl,and/or on one or more carbon atoms by alkyl, phenyl, phenylalkylhalogen, hydroxy, alkoxy, phenylalkoxy or oxo and can be partiallysaturated. Examples of such heteroaromatic residues are 2- or3-pyrrolyl, phenylpyrrolyl, for example, 4- or 5-phenyl-2-pyrrolyl,2-furyl, 2-thienyl, 2-imidazolyl, 2-, 3- or 4-pyridyl, 2-, 3- or5-indolyl, substituted 2-indolyl, for example, 1-methyl-, 5-methyl-,5-methoxy, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl,1-benzyl-2-indolyl, 1-benzyl-3-indolyl, 4,5,6,7-tetrahydro-2-indolyl,cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl,1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl,2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzthiazolyl,benz[e]indol-2-yl, 8-carbolin-3-yl and the like.

Examples of heteroaromatic-aliphatic hydrocarbon residues are 2- or3-pyrrolylmethyl, 2-, 3- or 4-pyridyl methyl, 2-(2-, 3- or4-pyridyl)ethyl, 4-imidazolylmethyl, 2-(4-imidazolyl)ethyl,2-indolylmethyl, 3-indolylmethyl, 2-(3-indolyl)ethyl, 2-quinolylmethyland the like.

A saturated 5- or 6-membered heterocycle has at least one carbon atom,1-3 nitrogen atoms and, optionally, one oxygen or sulfur atom as thering member(s) and is linked with the group --CO-- or --O--CO--,×N--CO--, >N--CS--, >N--CO--CO--, --SO₂ -- or >N--SO₂ -- through one ofits ring carbon atoms. The heterocycle can be substituted on one of itscarbon atoms or on a ring nitrogen atom with an alkyl group, forexample, methyl or ethyl, phenyl or phenylalkyl, for example, benzyl, oron one of its carbon atoms with hydroxy or oxo and/or can be benz-fusedon two adjacent carbon atoms. Examples of such heterocycles arepyrrolidin-3-yl, 4-hydroxypyrrolidin-2-yl, 5-oxopyrrolidin-2-yl,piperidin-2-yl, piperidin- -3-yl, 1-methylpiperidin-2-yl,1-methylpiperidin-3-yl. 1-methylpiperidin-4-yl, morpholin-2-yl,morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl,1,4-dimethylpiperazin-2-yl, 2-indolinyl, 3-indolinyl,1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl,1,2,3,4-tetrahydroisoquinol-1-, -3- or -4-yl, 1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl and the like.

Illustratively, the residues of an amino acid attached via the carboxylgroup include natural α-amino acids having the L-configuration; homologsof such amino acids. for example, in which the amino acid side-chain islengthened or shortened by one or two methylene groups and/or a methylgroup is replaced by hydrogen; substituted aromatic α-amino acids, forexample, substituted phenylalanine or phenylglycine in which thesubstituent can be alkyl, for example, methyl, halogen, (i.e., fluorine,chlorine, bromine or iodine), hydroxy, alkoxy, such as methoxy,alkanoyloxy, for example, acetoxy, amino, alkylamino, such asmethylamino, dialkylamino, such as dimethylamino, alkanoylamino, such asacetylamino or pivaloylamino, alkoxycarbonylamino, for example,t-butoxycarbonylamino, arylmethoxycarbonylamino, for example,benzyloxycarbonylamino, and/or nitro and can be present singly or inmultiples; benz-fused phenylalanine or phenylglycine such asα-naphthylalanine or hydrogenated phenylalanine or phenylglycine such ascyclohexylalanine or cyclohexyl-glycine; a 5- or 6-membered cyclicbenz-fused α-amino acid, for example, indoline-2-carboxylic acid or1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; a natural orhomologous α-amino acid in which a carboxy group in the side-chain ispresent in esterified or amidated form, for example, as an alkyl estergroup such as methoxycarbonyl or t-butoxycarbonyl or as a carbamoyl,alkylcarbamoyl such as methylcarbamoyl or as a dialkylcarbamoyl groupsuch as dimethylcarbamoyl, in which an amino group of the side-chain ispresent in acylated form, for example, as alkanoylamino such asacetylamino or pivaloylamino, as alkoxycarbonylamino such ast-butoxycarbonylamino or as an arylmethoxycarbonylamino group such asbenzyloxycarbonylamino, or in which a hydroxy group of the side-chain ispresent in etherified or esterified form, for example, as an alkoxygroup such as methoxy, as an arylalkoxy group such as benzyloxy or as alower alkanoyloxy group such as acetoxy, or epimers of such amino acids,that is, with the unnatural D-configuration. Examples of such aminoacids are glycine, alanine, valine, norvaline, leucine, isoleucine,norleucine, serine, homoserine, threonine, methionine, cysteine proline,trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine,4-nitrophenylalanine, 4-amino- phenylalanine, 4-chlorophenylalanine,β-phenylserine, phenylglycine, α-naphthylalanine, cyclohexylalanine,cyclohexylglycine, tryptophan, indoline-2-carboxylic acid,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid,asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamicacid, glutamic acid mono-t- butyl ester, glutamine, N-dimethylglutamine,histidine, arginine, lysine, N-t-butoxycarbonyllysine, δ-hydroxylysine,ornithine, N-pivaloylornithine, α, γ-diaminobutyric acid orα,β-diaminopropionic acid and the like. The residue of the amino acidattached via the carboxyl group can be substituted N-terminally byalkyl, for example, methyl or ethyl, in order to increase the stabilityof the compound of formula I against enzymatic degradation.

The residue of a di- or tri-peptide attached via the carboxyl groupconsists of two or three of the abovementioned amino acids.

The term "pharmaceutically usable salts" embraces salts with inorganicor organic acids, such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid,p-toluenesulfonic and the like. Such salts can be prepared readily bythese skilled in the art.

The compounds of formula I have at least three asymmetric carbon atomsand are therefore present in the form of optically pure diastereomersdiastereomeric mixtures, diastereomeric racemates or mixtures ofdiastereomeric racemates. The present invention embraces all forms.Diastereomer mixtures, diastereomeric racemates or mixtures ofdiastereomeric racemates can be separated using conventional methods,for example, column chromatography, thin-layer chromatography, HPLC andthe like.

Those compounds of formula I in which R¹ is hydrogen are preferred. R²preferably is imidazol-4 yl. Further. those compounds of formula I inwhich R³ is cyclohexylmethyl are preferred. Also preferred are thosecompounds of formula I in which R⁴ is vinyl or ethyl. Also preferred arethe compounds of formula I in which A is the group (a) or (b). R⁵preferably is phenyl or naphthyl, particularly phenyl. Preferred for R⁶are alkylcarbonylalkyl, cycloalkylcarbonylalkyl,heterocycloalkylcarbonylalkyl, aminocarbonylalkyl or substitutedaminocarbonylalkyl, preferably C₁ -C₄ -alkylcarbonylmethyl, C₅ -C₆-cycloalkylcarbonylmethyl, N-t-butoxycarbonylpyrrolidinylcarbonylmethylor aminocarbonylalkyl, which is disubstituted with C₁ -C₄ -alkyl or C₄-C₅ -alkylene optionally interrupted by an oxygen atom or which ismonosubstituted with aminoalkyl mono- or disubstituted withalkoxycarbonylalkyl or alkoxycarbonyl.

Furthermore, there are preferred the compounds of formula I in which Yrepresents the bivalent residue of phenylalanine, cyclohexylalanine,4-chlorophenylalanine or α-naphthylalanine, particularly phenylalanine,linked with Z at the N-terminal. Z preferably is acyl, particularly theresidue, linked with Y at the C-terminal, of a N- and/or α-methylatednatural amino acid having the L-configuration or an epimer of such anamino acid having the D-configuration or of a dipeptide from two of theabove-described amino acids or the group R^(b) --CO-- or R^(a) --O--CO--in which R^(a) is an optionally substituted, saturated or unsaturatedaliphatic, cyclo-aliphatic, cycloaliphatic-aliphatic hydrocarbon residuewith up to 18 carbon atoms, an optionally substituted aromatic,heteraromatic, aromatic-aliphatic or heteroaromatic-aliphatichydrocarbon residue with up to 18 carbon atoms or an optionallysubstituted, saturated 5- or 6-membered heterocycle and R^(b) ishydrogen or has the significance R^(a), particularly a residue, linkedwith Y at the C-terminal, of proline, prolylproline orhistidinylproline, whereby the amino group in each case is substitutedwith t-butoxycarbonyl, benzoxycarbonyl, isovaleryl or the group R^(b)--CO-- in which R^(b) is a heteroaromatic-aliphatic hydrocarbon residuewith up to 10 carbon atoms or a saturated 5- or 6-membered heterocycle.

From the above, it can be seen that there are particularly preferredthose compounds in which R¹ is hydrogen, R is imidazol-4-yl, R³ iscyclohexylmethyl, R⁴ is vinyl or ethyl, R⁵ is phenyl, and R⁶ is C₁ -C₄-alkyl-carbonylmethyl, C₅ -C₆ -cycloalkylcarbonylmethyl,N-t-butoxycarbonylpyrrolidinylcarbonylmethyl or amino-carbonylalkyl,which is disubstituted with C₁ -C₄ -alkyl or C₄ -C₅ -alkylene optionallyinterrupted by an oxygen atom or which is mono-substituted withaminoalkyl mono- or di-substituted with alkoxycarbonylalkyl oralkoxycarbonyl, or those compounds in which Y is the bivalent residue ofphenylalanine linked with Z at the N-terminal and Z is the residue ofproline, prolylproline or histidinylproline linked with Y at theC-terminal, in which the amino group in each case is substituted witht-butoxycarbonyl, benzoxycarbonyl, isovaleryl or the group R^(b) --CO--in which R^(b) is a heteroaromatic-aliphatic hydrocarbon residue with upto 10 carbon atoms or a saturated 5- or 6-membered heterocycle.

Especially preferred compounds of formula I are the following:

t-butyl (R)-2-[[(S)-α-[[(S)-1-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylate;

(2S,3S,5S)-2-(Boc-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol;

N-(S)-[(1S,2S.4S)-1-(cyclohexylmethyl-2-hydroxy.4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-3-methylbutyramido]-imidazole-4-propionamide;

t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate;

t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate;

t-butyl(S)-2-[[(R)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate;

(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[[[[(R)-α-2-hydroxy-l-(hydroxymethyl)-1-methylethyl]carbamoyl]methyl]hydrocinnamamido]imidazole-4-propionamide;

N-(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-γ-oxo-α-(1-naphthylmethyl)-4-morpholinebutyramide;t-butoxycarbonyl [2-[(R andS)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyramido]ethyl]glycine t-butyl ester;

(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]carbamoyl]methyl]hydrocinnamamido]imidazole-4-propionamide;

(S)-α-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide;

(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-2-[N-(morpholinocarbamoyl)3-phenyl-L-alanyl]amino]imidazole-4-propionamide;(S)-α-[(R)-α-(carbamoylmethyl)hydrocinnamamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide;

(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[(dimethylcarbamoyl)methyl]hydrocinnamamido]imidazole-4-propionamide;

(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy.4-isopropyl-5-hexenyl]-.alpha.-[(RS)-α-[(cyclopentylcarbonyl)methyl]hydrocinnamamido]imidazole-4-propionamide;

(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(RS)-α-[(cyclopenrylcarbonyl)methyl]hydrocinnamamido]imidazole-4-propionamide,and(2S,5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol.

The compounds of formula I in the form of optically pure diastereomers,diastereomer mixtures, diastereomeric racemates or mixtures ofdiastereomeric racemates as well as pharmaceutically usable saltsthereof can be prepared by

a) reacting a compound of the formula ##STR5## in which R¹, R², R³ andR⁴ have the meanings given above, with an acylating agent to yield thegroup ##STR6## in which R⁵, R⁶, Y, Z and the dotted line have themeanings given above,

b) reacting a compound of the formula ##STR7## in which R³ and R⁴ havethe meanings given above, with a compound of the formula ##STR8##wherein R¹, R² and A have the meanings given above, or an activatedderivative thereof, or

c) for the preparation of a compound of formula I in which R⁴ is ethyland the remaining symbols have the meanings given above, hydrogenating acompound of formula I in which R⁴ is vinyl and the remaining symbolshave the meanings given above, or

d) for the preparation of a compound of formula I in which R⁴ means1,2-dihydroxyethyl and the remaining symbols have the meanings givenabove, oxidizing a compound of formula I in which R⁴ means vinyl and theremaining symbols have the meanings given above, or

e) for the preparation of a compound of formula I in which A contains afree amino group, cleaving off the N-protecting group from acorresponding compound of formula I in which A contains a N-protectedamino group, or

f) if desired, separating a mixture of diastereomeric racemates into thediastereomeric racemates or optically pure diastereomers, or

g) if desired, separating a diastereomer mixture into the optically purediastereomers, or

h) if desired, converting a compound obtained into a pharmaceuticallyusable salt.

The acylation of a compound of formula II is effected according to knownmethods. Especially suitable acylating agents are activated acidderivatives such as esters, mixed esters, acid halides and acidanhydrides or mixed anhydrides. The reaction is carried out in anorganic solvent or solvent mixture which is inert under the reactionconditions, at a temperature between about 0° C. and room temperature.As solvents there can be used aromatic hydrocarbons such as benzene,toluene or xylene, chlorinated hydrocarbons such as methylene chlorideor chloroform, and ethers such as diethyl ether, tetrahydrofuran ordioxan, and the like. Where the acylating agent is a peptide, thereaction is effected under reaction conditions which are usual inpeptide chemistry, preferably in the presence of a condensation agentsuch as HBTU (O-benzotriazolyl-N,N,N',N'-tetramethyluroniumhexafluorophosphate), BOP (benzotriazol-1-yloxybis-(dimethylamino)phosphonium hexa- fluorophosphate), HOBT(N-hydroxybenzotriazole), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DCC(dicyclohexylcarbodiimide). EDC (N-ethyl-N'(3-dimethylaminopropyl)carbodiimide hydrochloride), Hunig base(ethyldiisopropylamine), or the like. The reaction is convenientlycarried out in an organic solvent or solvent mixture which is inertunder the reaction conditions, at a temperature between about 0° and 50°C. preferably at about room temperature. As solvents there can be used,especially, dimethylformamide, methylene chloride, acetonitrile,tetrahydrofuran, and the like.

The reaction of a compound of formula III with a compound of formula IVis also effected according to methods which are known per se in peptidechemistry, that is, under the same conditions as given above for thereaction of a compound of formula II with a peptide. Examples ofsuitable activated derivatives of a compound of formula IV are acidhalides, acid anhydrides, mixed anhydrides, esters, mixed esters, andthe like.

The hydrogenation of a compound of formula I in which R⁴ is vinyl isalso effected according to known methods, in an organic solvent orsolvent mixture which is inert under the reaction conditions, at atemperature between about room temperature and 50° C., preferably atroom temperature, in the presence of a noble metal catalyst such asplatinum or palladium, preferably palladium. Suitable solvents include,especially, alcohols such as methanol or ethanol, and the like.

The oxidation of a compound of formula I in which R⁴ is vinyl is alsoeffected according to methods known per se in an organic solvent orsolvent mixture which is inert under the reaction conditions, at atemperature between about room temperature and the boiling point of thesolvent or solvent mixture, preferably at about room temperature. Osmiumtetroxide is an especially suitable oxidizing agent. The preferredsolvent is pyridine.

The cleavage of the N-protecting group in accordance with processvariant (e) is also effected according to methods known in an organicsolvent or solvent mixture which is inert under the reaction conditions,at a temperature between about 0° C. and room temperature, with an acidsuch as hydrochloric acid, trifluoroacetic acid, and the like. Suitablesolvents are ethers such as tetrahydrofuran or dioxane, alcohols such asmethanol, or chlorinated hydrocarbons such as methylene chloride, andthe like.

The starting materials of formula II are part of the present invention.These compounds can be prepared by reacting a compound of formula IIIwith optionally N-methylated histidine, norleucine or norvaline. Thisreaction is also effected according to methods which are known inpeptide chemistry, that is, under the reaction conditions describedabove for the reaction of a compound of formula II with a peptide.

The starting materials of formula III are also novel and are an objectof the present invention. They can be prepared, for example, by reactingan aldehyde of the formula ##STR9## wherein B is an amino protectinggroup, preferably t-butoxycarbonyl or benzyloxycarbonyl, and R³ has themeaning given above, with a compound of the formula ##STR10## wherein Xis chlorine, bromine or iodine, preferably bromine, and R⁴¹ is phenyl,furyl or vinyl, in a Grignard reaction. This reaction is also effectedaccording to known methods, for example, in a solvent which is inertunder the reaction conditions, such as an ether, at a temperaturebetween about 0° and 50° C., preferably at room temperature.Subsequently, the amino protecting group B is cleaved off from thecompound, for example, with hydrochloric acid in dioxane at roomtemperature. Where a compound of formula III in which R⁴ is ethyl or1,2-dihydroxyethyl is desired, the product of the Grignard reaction ishydrogenated or oxidized according to known methods prior to thecleavage of the amino protecting group B under the reaction conditionsgiven for process variant (c). Suitable oxidizing agents are osmiumtetroxide, potassium permanganate, ruthenium tetroxide, and the like.The reaction is carried out in an organic solvent or solvent mixturewhich is inert under the reaction conditions, at a temperature betweenabout room temperature and 50° C. Suitable solvents are pyridine.aromatic hydrocarbons such as benzene, and the like.

The compounds of formula V are known or can be obtained by analogy tothe preparation of known compounds.

The compound of formula VI in which R⁴¹ is vinyl is known. The compoundsof formula VI in which R⁴¹ is phenyl or furyl are novel and constitutean aspect of the present invention.

A process for the preparation of a compound of formula III in which R⁴is phenyl, furyl or vinyl is set forth of each of Schemes I-IIIhereinafter. The preparation of the novel compounds of formula VI inwhich R⁴¹ is phenyl or furyl can also be carried out from Schemes II andIII. Precise reaction conditions are given in the working examples.##STR11##

The compounds of formula I and their pharmaceutically usable salts havean inhibitory activity on the natural enzyme renin. The latter passesfrom the kidneys into the blood and brings about the cleavage ofangiotensinogen, with the formation of the decapeptide angiotensin I,which is then cleaved in the lungs, the kidneys and other organs to theoctapeptide angiotensin II. Angiotensin II increases blood pressure notonly directly by arterial constriction, but also indirectly by theliberation of the sodium ion-retaining hormone aldosterone from theadrenal gland, with which is associated an increase in the extracellularfluid volume. This increase is attributed to the action of angiotensinII, itself, or to the heptapeptide angiotensin III which is formedtherefrom as a cleavage product. Inhibition of the enzymatic activity ofrenin brings about a decrease in the formation of angiotensin I and as aconsequence the formation of a smaller amount of angiotensin II. Thereduced concentration of this active peptide hormone is the actualreason for the blood pressure-lowering activity of renin inhibitors.

The activity of renin inhibitors is demonstrated by means of thefollowing in vitro test:

In Vitro Test With Pure Human Renin

The test is carried out in Eppendorf test tubes. The incubation mixtureconsists of (1) 100 μl of human renin in buffer A (0.1M sodium phosphatesolution, pH 7.4, containing 0.1% bovine serum albumin, 0.1% sodiumazide and 1 mM ethylenediaminetetraacetic acid), sufficient for a reninactivity of 2-3 ng of angiotensin I/ml/hr.; (2) 145 μl of buffer A; (3)30 μl of 10 μM human tetradecapeptide renin substrate (hTD) in 10 mMhydrochloric acid; (4) 15 μl of dimethyl sulfoxide with or withoutinhibitor and (5) 10 μl of a 0.03 molar solution of hydroxyquinolinesulfate in water.

The samples are incubated for 3 hours at 37° C. or 4° C. in triplicate.2×100 μl samples per experimental test tube are used in order to measurethe production of angiotensin I via RIA (standard radioimmunoassay;clinical assay solid phase kit). Cross reactivities of the antibody usedin the RIA are: angiotensin I 100%; angiotensin II 0.0013%; hTD(angiotensin I-Val-Ile-His-Ser-OH) 0.09%. The production of angiotensinI in determined by the difference between the experiment at 37° C. andthat at 4° C.

The following controls are carried out:

(a) Incubation of hTD samples without renin and without inhibitor at 37°C. and 4° C. The difference between these two values gives the basevalue of angiotensin I production.

(b) Incubation of hTD samples with renin, but without inhibitor at 37°C. and 4° C. The difference between these values gives the maximal valueof angiotensin I production.

In each sample, the base value of the angiotensin I production issubtracted from the angiotensin I production which is determined. Thedifference between the maximal value and the base value gives the valueof the maximal substrate hydrolysis (=100%) by renin.

The results are given as IC₅₀ values which denote that concentration ofthe inhibitor at which the enzymatic activity is inhibited by 50%. TheIC₅₀ values are determined from a linear regression curve from alogit-log plot.

The results obtained in this test are compiled in the following Table:

                  TABLE                                                           ______________________________________                                        Compound    IC.sub.50 values in μMol/lt.                                   ______________________________________                                        A           0.0035                                                            B           0.0003                                                            C           0.0090                                                            D           0.0075                                                            E           0.0079                                                            F           0.0040                                                            G           0.0150                                                            H           0.0041                                                            I           0.0460                                                            K           0.0170                                                            L           0.0070                                                            M           0.0210                                                            N           0.1400                                                            O           0.0120                                                            P           0.0460                                                            Q           0.0680                                                            R           0.0017                                                            ______________________________________                                        A = t-Butyl (R)-2-[[(S)-α-[[(S)-1-[(1S,2S,4S)-1-cyclohexyl-             methyl-2-hydroxy-4-isopropylhexyl]-2-imidazol-4-yl-ethyl]carba-               moyl]phenethyl]carbamoyl]-1-pyrrolidine-carboxylate;                          B = (2S,3S,5S)-2-(Boc--D--Pro--Phe--His--NH)-1-cyclo-                         hexyl-5-isopropyl-6-hepten-3-ol;                                              C = N-(S)-[(1S,2S,4S)-1-(cyclohexylmethyl-2-hydroxy-4-iso-                    propyl-5-hexenyl]-α-[(S)-α-3-methylbutyramido]-imidazole-         4-propionamide;                                                               D = t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-           hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-yl-                     ethyl]carbamoyl]phenethyl]carbamate;                                          E = t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-           hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]car-                 bamoyl]phenethyl]carbamate;                                                   F = t-butyl (S)-2-[[(R)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexyl-           methyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-                   ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate;                 G = (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-iso-                   propylhexyl]-α-[[[[(R)-α-2-hydroxy-1-(hydroxymethyl)-1-methyl-    ethyl]carbamoyl]methyl]hydrocinnamamido]imidazole-4-                          propionamide;                                                                 H = N-(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-iso-                propylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-γ-oxo-α-(1-naphth    yl-                                                                           methyl)-4-morpholinebutyramide;                                               I = t-butyloxycarbonyl [2-[(R and S)-3-[[(S)-1-[[(1S,2S,4S)-1-                (cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-              imidazol-4-ylethyl]-carbamoyl]-4-phenylbutyramido]  ethyl]glycine             t-butyl ester;                                                                K = (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-iso-                   propyl-5-hexenyl]-α-[(R)-α-[[[2-hydroxy-1-(hydroxymethyl)-        1-methylethyl]carbamoyl]methyl]hydrocinnamamido]imidazole-                    4-propionamide;                                                               L = (S)-α-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanamido]-N-                [(1S,2S,4S)-1-(cyclohexylmethyl-2-hydroxy-4-isopropyl-5-                      hexenyl]imidazole-4-propionamide;                                             M = (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-iso-                   propyl-5-hexenyl]-α-2-[N-(morpholinocarbamoyl)-3-phenyl-L-              alanyl]amino]imidazole-4-propionamide;                                        N = (S)-α-[(R)-α-(carbamoylmethyl)hydrocinnamamido]-N-            [(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-                     hexenyl]imidazole-4-propionamide;                                             O = (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-iso-                   propyl-5-hexenyl]-α-[(R)-α-[(dimethylcarbamoyl)-methyl]hydro-     9                                                                             cinnamamido]imidazole-4-propionamide;                                         P = (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-iso-                   propyl-5-hexenyl]-α-[(RS)-α-[(cyclopentyl-carbonyl)methyl]hydr    o-                                                                            cinnamamido]imidazole-4-propionamide;                                         Q = (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-iso-                   propylhexyl]-α-[(RS)-α-(cyclopentylcarbonyl)methyl]hydro-         cinnamamido]imidazole-4-propionamide and                                      R = (2S,5S)-2-(Boc--D--Pro--Pro--Phe--His--NH)-1-cyclo-                       hexyl-5-isopropyl-6-hepten-3-ol.                                          

The compounds of formula I as well as their pharmaceutically usablesalts can be used in the form of pharmaceutical preparations. Thepharmaceutical preparations can be administered enterally such asorally, for example, in the form of tablets, coated tablets, dragees,hard and soft gelatin capsules, solutions, emulsions or suspensions,nasally, for example, in the form of nasal sprays, or rectally, forexample, in the form of suppositories. However, the administration canalso be effected parenterally such as intramuscularly or intravenously,for example, in the form of injection solutions.

For the preparation of tablets, coated tablets, dragees and hard gelatincapsules, the compounds of formula I as well as their pharmaceuticallyacceptable salts can be processed with pharmaceutically inert, inorganicor organic excipients. Lactose, maize starch or derivatives thereof,talc, stearic acid or its salts, and so forth, can be used as suchexcipients for tablets, dragees and hard gelatin capsules.

Suitable excipients for soft gelatin capsules are, for example,vegetable oils, waxes, fats, semi-solid and liquid polyols, and soforth.

Suitable excipients for the preparation of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, and soforth.

Suitable excipients for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, and so forth.

Suitable excipients for suppositories are, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, and so forth.

Moreover, the pharmaceutical preparations can contain preserving agents,solubilizers, viscosity-increasing substances, stabilizing agents,wetting agents, emulsifying agents, sweetening agents, coloring agents,flavoring agents, salts for varying the osmotic pressure, buffers,coating agents or antioxidants. They can also contain still othertherapeutically useful substances.

In accordance with this invention, the compounds of formula I as well astheir pharmaceutically acceptable salts can be used in the control orprevention of high blood pressure and cardiac insufficiency. The dosagecan vary within wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration there should suffice a daily dosage of about 3 mgto about 3 g, preferably about 10 mg to about 1 g, for example,approximately 300 mg per person, divided in preferably 1-3 unit doses,which can be of the same amount. However, the upper limit just given canalso be exceeded when this is found to be indicated. Usually, childrenreceive half of the dosage of adults.

The following Examples are intended to illustrate the present invention,but are not intended to be limiting in any manner. All temperatures aregiven in degrees Celsius. The following abbreviations for amino acidsand amino acid derivatives are used:

H-His-OH=L-histidine

H-Phe-OH=L-phenylalanine

H-Phe^(R) His-OH=N-[(S)-2-amino-3-phenylpropyl]--L-histidine

H-Pro-OH=L-proline

H-Ser-OH=L-serine

H-Tyr-OH=L-tyrosine

Further abbreviations:

Boc=t-butoxycarbonyl

Bom=benzyloxymethyl

IVA=isovaleryl

OBz=benzyloxy

OMe=methoxy

Pip=piperidinyl

Fmoc=9-fluorenylmethoxycarbonyl

t-Bu=t-butyl

EXAMPLE 1

A mixture of 313 mg 1.18 mmol) of t-butoxycarbonyl-L-phenylalanine. 460mg (1.18 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,0.15 ml (1.18 mmol) of 4-ethylmorpholine, 320 mg (2.36 mmol) of HOBT and292 mg (1.42 mmol) of DCC in 20 ml of dimethylformamide was stirred atroom temperature overnight. Thereafter, the separated precipitate wasfiltered off and the solvent was evaporated in a high vacuum. Theresidue was dissolved in ethyl acetate and then washed in successionwith 2N sodium bicarbonate solution, saturated ammonium chloridesolution, again with 2N sodium bicarbonate solution and again withsaturated ammonium chloride solution. After drying the organic solutionover sodium sulfate, the solvent was evaporated under reduced pressureand, for purification, the residue (870 mg) was chromatographed on 30 gof silica gel using a 20:1:0.1 mixture of methylene chloride, methanoland ammonia as the eluting agent. Crystallization of the thus-obtainedcrude product from methylene chloride/ether yielded 410 mg of t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate,melting point 161°.

The(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideused as the starting material was prepared as follows:

315.3 g (1.28 mmol) of t-butoxycarbonyl-L-phenylalanine methyl esterwere hydrogenated according to the method of J. Boger et al. in J. Med.Chem., 28, 1779 (1985) in the presence of 5% rhodium on aluminum oxideat room temperature and 440 kPa, to obtain 315.3 g of2-t-butoxycarbonylamino-3-cyclohexylpropionic acid methyl ester as anoil, which was used directly in the next step.

750 ml (750 mmol) of a 20% solution of diisobutylaluminum hydride inhexane were added dropwise at -75° C. in the course of 90 minutes to85.61 g (300 mmol) of 2-t-butoxycarbonylamino-3-cyclohexylpropionic acidmethyl ester in 1.2 1 of toluene. After completion of the addition, thereaction mixture was stirred at -75° for a further 10 minutes. Therewere subsequently added dropwise in each case within 25 minutes, at atemperature of -75° to -70°, first 70 ml of methanol and then 840 ml ofsaturated potassium sodium tartrate solution. The milky reactionsolution, warmed slowly to room temperature, was thereafter extractedwith ether and the extracts were dried and evaporated, whereby 82 g of2-t-butoxycarbonylamino-3-cyclohexylpropyl aldehyde was obtained as anoil, which was used in the next step without further purification.

A solution of 179.7 g (1.01 mol) of 4-bromo-3-isopropyl-1-butene (whichwas prepared according to the method of R. G. Helmquist in TetrahedronLetters, 2533 (1982)) in 900 ml of ether was added dropwise within 2.5hours to 24.65 g of magnesium shavings in 300 ml of ether, in an argonatmosphere, and at a temperature between 30° and the reflux temperatureof the solvent. After completion of the addition, the reaction mixturewas heated to reflux for 3.5 hours. To the reaction mixture, cooled to-60° C. was added dropwise within 75 minutes a solution of 82 g of2-t-butoxycarbonylamino-3-cyclohexylpropyl aldehyde in 900 ml of ether,with the temperature at to -60° to -70°. After completion of theaddition, the cooling bath was removed and the reaction mixture wasstirred at room temperature for 21 hours under argon. The mixture wasthen cooled to 5° and 225 ml of a saturated ammonium chloride solutionwas added cautiously while stirring, upon which the temperature rose to20°. The two phases were separated and the organic phase was dried oversodium sulfate and evaporated with 127.5 g of a yellow oil beingobtained. Chromatographic separation of this oil on 2.5 kg of silica gelwith methylene chloride which contained 2.5% ether as the eluting agentyielded 33.9 g of(αS,βS)-β-t-butoxycarbonylamino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol,13.62 g of(αS,βS)-β-t-butoxycarbonylamino-α-[(R)-2-isopropyl-3-butenyl]cyclohexanepropanol,as well as 35.5 g of a mixture of both of the above-named diastereomersin the form of oils, MS: 354 (M+H)⁺.

1.0 g (2.83 mmol) of(αS,βS)-β-t-butoxycarbonyl-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanolwas dissolved in 20 ml of 2.2N hydrogen chloride in dioxane and stirredat room temperature for 2 hours. Thereafter, the reaction mixture wasevaporated and treated twice in succession with toluene and then againevaporated to dryness. There was obtained thin-layer chromatographicallypure (αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol inthe form of the hydrochloride, which was used directly in the next step.

1.7 g (2.83 mmol) of N-α-N-im-Bis-Fmoc-L-histidine and 0.82 g (2.83mmol) of(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanolhydrochloride in 20 ml of dimethylformamide were treated with 0.36 ml of4-ethylmorpholine and 0.77 g of HOBT and cooled in an ice bath. 0.7 g ofDCC was added to the cooled solution and the mixture was stirredovernight under an argon atmosphere without removing the ice bath, thereaction mixture being allowed to warm slowly to room temperature.Thereafter, the separated precipitate was filtered off and the filtratewas evaporated in a high vacuum. The residue was poured onto ice and 70ml of a 2N sodium bicarbonate solution and extracted three times with150 ml of ethyl acetate each time. The organic extracts were washed oncewith ice and 70 ml of saturated ammonium chloride solution, once with 70ml of ice and 2N sodium bicarbonate solution, and once with 70 ml ofsaturated sodium chloride solution, then dried over magnesium sulphateand evaporated. The crude product (2.31 g) obtained in this manner wasstirred at room temperature for 3 hours in 3 ml of piperidine and 75 mlof methylene chloride. The mixture was then evaporated at about 30° andthe residue was triturated with 60 ml of hexane, to obtained 1.44 g of asolid which was chromatographed over 120 g of silica gel with a 12:1:0.1mixture of methylene chloride, methanol and ammonia. Two-foldrecrystallization of the crude product obtained from hexane yielded 580mg of thin-layer chromatographically pure(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideas crystals, melting point 73°.

EXAMPLE 2

130 mg (0.24 mmol) of t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenethyl]carbamate were dissolved in 30 ml of methanol and hydrogenated at roomtemperature for 1.5 hours in the presence of 65 mg ofpalladium-on-carbon (5%). After completion of the hydrogen uptake, thecatalyst was filtered off and the filtrate was evaporated.Crystallization of the residue from ether/hexane yielded 110 mg oft-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate as crystals, melting point 101°.

EXAMPLE 3

A mixture of 83 mg (0.345 mmol) of dibenzylacetic acid, 90 mg (0.23mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. 0.045 ml(0.345 mmol) of 4-ethylmorpholine, 93 mg (0.69 mmol) of HOBT and 85 mg(0.41 mmol) of DCC in 15 ml of dimethylformamide was stirred at roomtemperature overnight. Thereafter, the separated precipitate wasfiltered off and the filtrate was evaporated to dryness. The residue wasthen dissolved in ethyl acetate and the solution was washed insuccession with 2N sodium bicarbonate solution, saturated ammoniumchloride solution, again with 2N sodium bicarbonate solution and againwith saturated ammonium chloride solution, dried over sodium sulfate andevaporated. The residue was chromatographed on 30 g of silica gel with a14:1:0.1 mixture of methylene chloride, methanol and ammonia.Crystallization of the residue from methylene chloride/methanol/hexaneyielded 60 mg of (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-(2,2-dibenzylacetamido)imidazole-4-propionamide,melting point 98°.

EXAMPLE 4

A mixture of 880 mg (2.5 mmol) of(S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-imidazole-4-propionamide.1.99 g (7.5 mmol) of t-butoxycarbonyl-L-phenylalanine. 1.05 ml (7.5mmol) of triethylamine and 3.32 g (7.5 mmol) of BOP in 100 ml ofacetonitrile was stirred at room temperature for 6 days. Thereafter, thesolvent was evaporated and the residue was dissolved in ethyl acetateand washed in succession with 2N sodium bicarbonate solution, saturatedammonium chloride solution, again with 2N sodium bicarbonate solutionand again with saturated ammonium chloride solution. The organicsolution was dried over sodium sulfate and evaporated and the residuewas triturated twice with hexane. The residue was chromatographed on 100g of silica gel with a 98:2 mixture of chloroform and methanol.Recrystallization of the thus-obtained crude product from methylenechloride and hexane yielded 400 mg of t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamateas a white powder, melting point 82°.

The(S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamideused as the starting material was prepared as follows:

t-Butoxycarbonyl-L-leucine methyl ester was reduced withdiisobutylaluminium hydride in an analogous manner to that described inExample 1 to give 2-t-butoxycarbonylamino-4-methyl-valeraldehyde, whichwas used directly in the next step without further purification.

A solution of 142.3 g (691 mmol) of 4-bromo-3-isopropyl-1-butene in 600ml of ether was added dropwise within 75 minutes to 16.8 g of magnesiumshavings in 980 ml of ether under argon and at room temperature. Aftercompletion of the addition, the reaction mixture was heated to refluxfor 3.25 hours and thereafter cooled to -60°. There was added dropwisewithin 75 minutes a solution of 50.1 g (203.8 mmol) of2-t-butoxycarbonylamino-4-methyl-valeraldehyde in 600 ml of ether. Aftercompletion of the addition, the cooling bath was removed and thereaction mixture was stirred at room temperature for 17 hours. Themixture was then cooled to 5° and 150 ml of a saturated ammoniumchloride solution were added dropwise while stirring, upon which thetemperature rose to 20°. After a working-up analogous to that describedin Example 1, there was obtained 88.4 g of a yellow oil, which waschromatographed on 2.5 kg of silica gel with a 98:2 mixture of methylenechloride and ether. After repeated chromatography of the mixed fractionsunder the same conditions, there was obtained a total of 30.2 g of pure,thin-layer chromatographically uniform(4S)-t-butoxy-carbonylamino-(5S)-hydroxy-(7S)-isopropyl-2-methyl-8-nonene. MS: 240 (M-t-butoxy)⁺.

The t-butoxycarbonyl group was cleaved off with hydrogen chloride indioxane in an analogous manner to that described in Example 1 toobtained (4S)-amino-(5S)-hydroxy-(7S)-isopropyl-2-methyl-8-nonene, whichwas was used directly in the next step without further purification.

A mixture of 550 mg (1.75 mmol) of(4S)-amino(5S)-hydroxy-(7S)-isopropyl-2-methyl-8-nonene, 1.547 mg (2.65mmol) of N-α-N-im-Bis-Fmoc-L-histidine, 2.323 g of BOP and 0.73 ml oftriethylamine in 30 ml of acetonitrile was stirred at room temperaturefor 4 days. Thereafter, the solvent was evaporated under reducedpressure and the residue was worked-up in a manner analogous to thatdescribed in Example 1. Chromatography of the crude product on 500 g ofsilica gel with a 140:5:0.5 mixture of methylene chloride, methanol andammonia yielded 950 mg of fluoren-9-ylmethyl[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamate as an oil, which was used directly in the next step, MS: 369(M+H)⁺.

1.3 g of fluoren-9-ylmethyl[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamatein 30 ml of methylene chloride and 2 ml of piperidine were stirred atroom temperature for 1.5 hours. Thereafter, the solvent was evaporatedand the residue was triturated with hexane. The(S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-imidazole-4-propionamideso obtained was used in the next step without further purification.

EXAMPLE 42

A mixture of 460 mg (1.18 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,313 mg (1.18 mmol) of t-butoxycarbonyl-L-phenylalanine, 0.15 ml (1.18mmol) of 4-ethylmorpholine, 320 mg (2.36 mmol) of HOBT and 292 mg (1.42mmol) of DCC in 20 ml of dimethylformamide was stirred at roomtemperature for 18 hours and subsequently worked-up in the usual manner.Chromatography of the residue on 30 g of silica gel using a 20:1:0.1mixture of methylene chloride, methanol and ammonia as the eluting agentyielded 410 mg of crystals of melting point 161°.

2.5 g of the above compound were dissolved in 50 ml of 2.2N hydrogenchloride in dioxane and stirred at room temperature for 6 hours.Thereafter, the reaction mixture was evaporated under reduced pressureand the residue was purified by chromatography on silica gel with a190:10:1 mixture of methylene chloride, methanol and ammonia, to obtainN-[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideas a uniform material. MS: 538 (M+H)⁺.

EXAMPLE 6

The following compounds were prepared in an analogous manner to thatdescribed in Example 1:

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand α-benzyltetrahydro-oxo-4H-1,4-oxazinepropionic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(RS)-α-(morpholinocarbonyl)hydrocinnamamido)imidazole-4-propionamideas crystals of melting point 94° (from methylene chloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand t-butoxycarbonyl-D-proline, the(2S,3S,5S)-2-(Boc-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas crystals of melting point 132° (from methylenechloride/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand t-butylacetic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(3,3-dimethylbutyramido)hydrocinnamoyl]-imidazole-4-propionamideas crystals of melting point 105° (dec.; from methylenechloride/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand isovaleric acid, theN-(S)-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-3-methylbutyramido]imidazole-4-propionamideas a foam, MS: 622 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand (S)-α-[[(S)-2-benzylamino-3-phenylpropyl]amino]hydrocinnamic acid,the benzyl[α-[[[α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]amino]methyl]phenethyl]carbamateas crystals of melting point 89° (from methylene chloride/ether/hexane);

From(S)-α-amino-N-[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]hydrocinnamamide,which was obtained from t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazole-4-ylethyl]carbamoyl]-phenethyl]carbamate by allowing to stand at room temperature for 18 hours in 0.3Nmethanolic hydrochloric acid, and cyclopentanecarboxylic acid, the(S)-α-[(RS)-cyclopentanecarboxamido]-N-[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]hydrocinnamamideas crystals of melting point 185° (dec,; from methanol/methylenechloride/hexane):

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propianamideand benzyl [(methylthio)formimidoyl] carbamate¹, the benzyl[N-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenethyl]amidino]carbamate as a foam, MS: 714 (M+H)⁺ ;

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propianamideand t-butoxycarbonylaminovaleric acid, the t-butyl[4[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-butyl]carbamate as crystals of melting point 110° (from methylenechloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand N-t-butoxycarbonyl-N-methyl-L-phenylalanine, the t-butyl[(S)-α-[[(S)-1-(S)-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]methylcarbamate as crystals of melting point 93° (from ether/hexane);

From(S)-α-amino-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand t-butoxycarbonyl-L-phenylalanine, the(2S,3S,5R)-2-(Boc-phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol asa foam. MS 638 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand dibenzsuberaneacetic acid², theN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[2-(10,11-dihydro-5H-dibenzo(a,d]cyclohepten-5-yl)acetamido]imidazole-4-propionamideas crystals of melting point 135° (from methylenechloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 3-(3-indolyl)propionic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-indol-3-ylpropionamido)imidazole-4-propionamideas a solid of melting point 122° (from ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand benzylmalonic acid monoamide, the(S)-α-[(RS)-α-carbamoylhydrocinnamamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideas a foam, MS: 566 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand (S)-α-benzyl-2,5-dimethylpyrrol-1-acetic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(2,5-dimethylpyrrol-1-yl)hydrocinnamamido]imidazole-4-propionamideas crystals of melting point 93° (from ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand α-[(2-hydroxyethyl)carbamoyl]hydrocinnamic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(RS)-α-[(2-hydroxyethyl)carbamoyl]hydrocinnamamido]imidazole-4-propionamideas a foam, MS: 610 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand α-[[2-(dimethylamino)ethyl]carbamoyl]hydrocinnamic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl-.alpha.-[(RS)-α-[[2-(dimethylamino)ethyl]carbamoyl]hydrocinnamamido]imidazole-4-propionamideas a foam, MS: 637 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand dibenzyl-cyanoacetic acid, the(S)-α-(α-benzyl-α-cyanohydrocinnamamido)-N-[(1S,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide as crystals of meltingpoint 105° (from ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand benzyl-cyanoacetic acid, the(RS)-α-cyano-N-[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]hydrocinnamamide as crystalsof melting point 97° (from methylene chloride/ether/hexane;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand indole-2-carboxylic acid, theN-[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-yl-ethyl]-2-benzimidazolecarboxamideas crystals of melting point 123° (from methylenechloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand isovaleric acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-methylbutyramido)imidazole-4-propionamideas a foam, MS; 622 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand α-benzyl- -oxo-1-pyrrolidinepropionic acid, theN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[(RS)-α-(1-pyrrolidinylcarbonyl)hydrocinnamamido]imidazole-4-propionamideas crystals of melting point 89° (from methylene chloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand α-[(benzyloxy)carbamoyl]hydrocinnamic acid, the(S)-α-[(RS)-α-[(benzyloxy)carbamoyl]hydrocinnamamido]-N-[(1S,2S,4S)-1-cyclohexyl-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideas crystals of melting point 104° (from methylenechloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 1-[α-(methoxycarbonyl)hydrocinnamoyl]-4-piperidinecarboxylic acid,the methyl(RS)-α-[[4-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]piperidino]carbonyl]hydrocinnamateas crystals of melting point 89° (from methylene chloride/ether/hexane).

The acids used as starting materials are either known and obtainedcommercially or were prepared as follows:

α-Benzyltetrahydro-8-oxo-4H-1,4-oxazinepropionic acid benzylmalonic acidmonomethyl ester which in turn had been prepared according to knownmethods³, was amidated with morpholine according to usual methods andsubsequently hydrolyzed with 1N sodium hydroxide solution to giveα-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, MS: 264 (M+H)⁺.

(S)-α-[[(S)-2-Benzylamino-3-phenylpropyl]amino]hydrocinnamic acid

In a manner analogous to the preparation of Boc-Phe^(R) His(Bom)-OHdescribed in Example 26, there was prepared from N-benzyl-Phe-Phe-OMe bysulfurization of the amide carbonyl group, desulfurization thereof withRaney-nickel and subsequent hydrolysis of the ester obtained, the(S)-α-[[(S)-2-benzylamino-3-phenylpropyl]amino]hydrocinnamic acid whichwas used directly in the next step.

t-Butoxycarbonylaminovaleric acid

5-Aminovaleric acid was converted under Schotten-Baumann conditions withdi-t-butyl carbonate in the usual manner into the correspondingN-protected acid, melting point 48°-50° (from ether/hexane).

Benzylmalonic acid monoamide

Benzylmalonic acid monomethyl ester was amidated with ammonia in theusual manner and the 2-benzyl-2-formamidoacetic acid methyl esterobtained was hydrolyzed with 1N sodium hydroxide solution in a 9:1mixture of methanol and water within 30 minutes to benzylmalonic acidmonoamide, Rf: 0.15 in a 90:10:1:0.5 mixture of chloroform, methanol,water and acetic acid.

(S)-α-Benzyl-2,5-dimethylpyrrole-1-acetic acid

L-phenylalanyl methyl ester hydrochloride was converted into thecorresponding free base by shaking with a sodium bicarbonate solution inether and heated to 100° for 2.5 hours in glacial acetic acid withacetonylacetone. Thereafter, the solvent was evaporated and the residuewas filtered with toluene over silica gel, to obtain methyl(S)-α-benzyl-2,5-dimethylpyrrole-1-acetate, MS: 258 (M+H)⁺. The ester soobtained was allowed to stand at room temperature for 1.5 hours with 1Nsodium hydroxide solution in a 9:1 mixture of methanol and water. Afterextracting the aqueous solution with ether and washing the organicphase, there was obtained (S)-α-benzyl-2,5-dimethylpyrrole-1-aceticacid, MS: 244 (M+H)⁺, which was used directly in the next step.

α-[(2-Hydroxyethyl)carbamoyl]hydrocinnamic acid

In a manner analogous to that described above forα-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonicacid monomethyl ester was amidated with ethanolamine and the compoundobtained was saponified to α-[(2-hydroxyethyl)carbamoyl]hydrocinnamicacid, MS: 251 (M)⁺, which was used directly in the next step.

α-[[2-(Dimethylamino)ethyl]carbamoyl]hydrocinnamic acid

In a manner analogous to that described above forα-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonicacid monomethyl ester was amidated with N,N-dimethylaminoethylamine andsubsequently saponified toα-[[(2-(dimethylamino)ethyl]carbamoyl]hydrocinnamic acid, [MS: 265(M+H)⁺ ], which was used directly in the next step.

Dibenzyl-cyanoacetic acid

Cyanoacetic acid ethyl ester was dibenzylated in the presence of sodiumethylate with excess benzyl bromide in ethanol to givedibenzyl-cyanoacetic acid ethyl ester, which was hydrolyzed with 1Nsodium hydroxide solution in a 9:1 mixture of methanol and water to givedibenzyl-cyano-acetic acid, melting point 194° (from methylene chloride/methanol/hexane).

Benzyl-cyanoacetic acid

Cyanoacetic acid ethyl ester was alkylated with benzyl bromide in thepresence of sodium ethylate in ethanol to give benzyl-cyanoacetic acidethyl ester [MS: 203 (M)⁺ ] which was then subsequently hydrolyzed with1N sodium hydroxide solution in a 9:1 mixture of methanol and water togive the corresponding acid. Recrystallization of the crude product frommethylene chloride/hexane yielded benzyl-cyanoacetic acid as crystals ofmelting point 97°.

α-Benzyl-β-oxo-1-pyrrolidineoropionic acid

In a manner analogous to that described forα-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonicacid monomethyl ester was amidated with pyrrolidine and the productobtained was hydrolyzed to α-benzyl-β-oxo-1-pyrrolidinepropionic acid,which was used directly in the next step, MS: 248 (M+H)⁺.

α-[(Benzyloxy)carbamoyl]hydrocinnamic acid

In a manner analogous to that described forα-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonicacid monomethyl ester was amidated with O-benzylhydroxylamine and theresulting product [MS: 314 (M+H)⁺ ] was saponified with 1N sodiumhydroxide solution in a 9:1 mixture of methanol and water to thecorresponding acid. Recrystallization of the crude product frommethanol/methylene chloride/ether yieldedα-[(benzyloxy)carbamoyl]hydrocinnamic acid of melting point 147°.

1-[α-(Methoxycarbonyl)hydrocinnamoyl]-4-piperidine-carboxylic acid

In a manner analogous to that described for the preparation ofα-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonicacid monomethyl ester was amidated with piperidine-4-carboxylic acidethyl ester and the resulting compound [MS: 347 (M)⁺ ]was saponifiedwith 1N sodium hydroxide solution in a mixture of methanol and water at0° for 2 hours. The crude product obtained was purified bychromatography on silica gel with a 95:5:2 mixture of chloroform,ethanol and ethyl acetate and recrystallized from a mixture of methanol,methylene chloride and ether, to yield1-[α-(methoxycarbonyl)hydrocinnamoyl]-4-piperidinecarboxylic acid,melting point 138°.

EXAMPLE 7

In a manner analogous to that described in Example 1,N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propianamidewas reacted with di-t-butoxycarbonyl-aminoethylglycine. Chromatographicpurification and recrystallization of the crude product yieldeddi-t-butyl N-[[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenylethyl]carbamoyl]methyl]ethylenedicarbamate,melting point 109°.

150 mg ofN-[[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenylethyl]carbamoyl]-methyl]ethylenedicarbamatewere dissolved in 0.3N hydrochloric acid in methanol and allowed tostand at room temperature overnight. Thereafter, the solvent wasevaporated and the residue was precipitated from methanol/ethyl acetate,to obtain(S)-α-[(S)-α-[-2-[(2-amino-ethyl)amino]acetamido]hydrocinnamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamidetrihydrochloride, MS: 638 (M+H)⁺.

The di-t-butoxycarbonyl-aminoethylglycine used as the starting materialwas prepared as follows:

N-(2-Aminoethyl)glycine was prepared according to the method describedby E. P. Heimer in Int. J. Pept. Prot. Res., 23, 203 (1984) andconverted in a known manner under Schotten-Baumann conditions withdi-t-butyl carbonate into the corresponding N-protected acid, MS: 319(M+H)⁺.

EXAMPLE 8

60 mg of(2S,3S,5S)-2-(Boc-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olwere dissolved in 10 ml of 2.1N hydrogen chloride in dioxane and stirredat room temperature for 1.5 hours. The solvent was then evaporated andthe residue was treated twice in succession with toluene and thereafteragain evaporated to dryness. Crystallization of the thus-obtainedresidue from methylene chloride/ether/hexane yielded 40 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[(S)-α-(D-prolylamino)hydrocinnamamido]-imidazole-4-propionamidedihydrochloride as white crystals of melting point 159°.

EXAMPLE 9

N-Methyl-L-histidine was converted with benzyl alcohol in the presenceof hydrochloric acid at room temperature into the corresponding benzylester and this was reacted according to the procedure described by D. H.Rich et al. in Proc. 9^(th) American Pept. Symp.. Toronto 1985. page217, with t-butoxycarbonyl-L-phenylalanine in the usual manner.Thereafter, the N-[N-t-butoxycarbonyl)-3-phenylL-alanyl]-N-methyl-L-histidine benzyl ester obtained was hydrogenatedfor one hour in the presence of 5% palladium on carbon, to obtainN-[N-(t-butoxy-carbonyl)-3-phenyl L-alanyl]-N-methyl-L-histidine, Rf:0.2 in a 80:20:3:3 mixture of chloroform, methanol, water and aceticacid. This compound was then reacted in the usual manner with(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol. Thecrude product obtained was then chromatographed on silica gel with a20:1:0.1 mixture of methylene chloride, methanol and ammonia, upon whichthe two epimeric compounds were separated. Recrystallization of thecrude product obtained from the first fraction from ether/ methylenechloride/hexane yielded t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoyl]-phenylethyl] carbamateas white crystals of melting point 95°.

From the second fraction, there was obtained after recrystallizationfrom ether/methylene chloride/hexane the epimeric compound t-butyl[(S)-α-[[(R)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoyl]phenethyl]carbamate as white crystals of melting point 85°.

In a manner analogous to that described above,N-t-butoxycarbonyl-N-methyl-L-phenylalanine was reacted withN-methyl-L-histidine benzyl ester according to the method described byRich et al., the ester obtained was subsequently hydrogenated to thecorresponding acid, and this was reacted in the usual manner with(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol.Chromatographic purification of the crude product on silica gel with a140:1:0.1 mixture of methylene chloride, methanol and ammonia yieldedthin-layer chromatographically pure t-butyl[(S)-α-[[(S)-α-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoyl]phenethyl]-methylcarbamate in the form of a foam, MS: 666 (M+H)⁺.

EXAMPLE 10

150 mg (0.20 mmol) of t-butyl2-benzyl-2-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]carbamate were dissolved in 10 ml of 0.3N methanolic hydrochloric acidand allowed to stand at room temperature overnight. Thereafter, thesolvent was evaporated and, for purification, the residue waschromatographed on 30 g of silica gel with a 20:1:0.1 mixture ofmethylene chloride, methanol and ammonia as the eluting agent.Recrystallization of the thus-obtained crude product from methylenechloride/ether/hexane yielded(S)-α-(3-amino-2,2-dibenzylpropionamido)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideas white crystals of melting point 89°.

The t-butyl2-benzyl-2-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]carbamate used as the starting material was prepared as follows:

Dibenzylcyanoacetic acid methyl ester was reduced with Raney-nickel inmethanolic ammonia to dibenzylmethylaminoacetic acid ethyl ester [MS:284 (M) ], which was then protected at the amino group with di-t-butylcarbonate in triethylamine in the usual manner. The ester [MS: 398(M+H)⁺ ]obtained in this manner was subsequently saponified with 1Nsodium hydroxide solution in a mixture of methanol and water to thecorresponding acid which, after recrystallization frommethanol/methylene chloride/hexane, was isolated as crystals of meltingpoint 157°. The acid was thereafter reacted in the usual manner with(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideto give t-butyl2-benzyl-2-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]carbamate. Recrystallization from methylene chloride/hexane/etheryielded white crystals of melting point 97°.

EXAMPLE 11

150 mg of(S)-α-[(RS)-α-[(benzyloxy)carbamoyl]-hydrocinnamamido]-N-[(1S,2S,4S)-1-cyclohexyl-2-hydroxy4-isopropyl-5-hexenyl]imidazole-4-propionamide were hydrogenated in thepresence of 5% palladium on carbon in methanol for 3 hours. Aftercompletion of hydrogen uptake, the catalyst was filtered and thefiltrate was evaporated. Recrystallization of the residue frommethanol/methylene chloride/ether yielded(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-4-ethyl-2-hydroxy-5-methylhexyl]-.alpha.-[(RS)-α-(hydroxycarbamoyl)hydrocinnamamido]imidazole-4-propionamideas white crystals of melting point 123°.

EXAMPLE 12

120 mg of t-butyl[(S)-α-[[(S)-1-(S)-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]methyl carbamate weredissolved in 0.3N methanolic hydrochloric acid and stirred at roomtemperature overnight. Thereafter, the solvent was evaporated underreduced pressure and the residue was treated with t-butylacetyl chlorideand triethylamine in tetrahydrofuran and allowed to stand at roomtemperature overnight. After the usual working-up, chromatographicpurification on silica gel using a 20:1:0.1 mixture of methylenechloride, methanol and ammonia, and recrystallization from ether/hexane,there was obtained(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(N,3,3-trimethylbutyramido)hydrocinnamamido]imidazole-4-propionamideas white crystals of melting point 126°.

EXAMPLE 13

The following compounds were prepared in a manner analogous to thatdescribed in Example 1:

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenylL-alanyl)imidazole-4-propionamide and 3-(4-hydroxyphenyl)propionic acid,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(p-hydroxyhydrocinnamamido)-hydrocinnamamido]imidazole-4-propionamideas white crystals, melting point 120° (from methylenechloride/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand nicotinic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-nicotinamidohydrocinnamamido]imidazole-4-propionamideas a solid, MS: 643 (M+H)⁺ ;

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenylL-alanyl)imidazole-4-propionamide and 3-(4-pyridyl)acrylic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[(S)-α-[(E)-4-pyridineacrylamido]-hydrocinnamido]imidazole-4-propionamideas yellowish crystals, melting point 135° (dec.; from methylenechloride/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 3-(3-pyridyl)acrylic acid, the (S)-[(1S,2S,4S)1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[(S)-α-(3-pyridineacrylamido)-hydrocinnamamido]imidazole-4-propionamideas yellowish crystals, melting point 141° (from methylenechloride/ether);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 3-(4-imidazolyl)acrylic acid (urocanic acid), the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(imidazol-4-acrylamido)hydrocinnamamido]imidazole-4-propionamideas white crystals, melting point 150°-152° (from methylenechloride/methanol/ether);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand D-(-)-quinic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(1,3,4,5-tetrahydroxycyclohexanecarboxamido)hydrocinnamamido]imidazole-4-propionamideas a white solid, MS: 712 (M+H)⁺ ;

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand quinaldic acid, theN-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]-2-quinolinecarboxamideas a white solid, MS: 693 (M+H)⁺ ;

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand levulinic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(4-oxavaleramido)hydrocinnamamido]imidazole-4-propionamideas white crystals, melting point 150° (dec.; from methylenechloride/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenylL-alanyl)imidazole-4-propionamide and 3-pyridylacetic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(3-pyridineacetamido)hydrocinnamamido]-imidazole-4-propionamideas white crystals, melting point 195° (dec.; from methanol/methylenechloride/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 4-chlorocinnamic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α[(S)-α-(4-chlorocinnamamido)hydrocinnamamido]imidazole-4-propionamideas white crystals, melting point 139° (from methylenechloride/methanol/ether);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand trans-4-nitrocinnamic acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(4-nitrocinnamamido)hydrocinnamamido]imidazole-4-propionamideas yellowish crystals, melting point 120° (dec.; from methylenechloride/methanol/ether);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand fumaric acid monoethyl ester, the ethyl3-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-b4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]acrylateas white crystals, melting point 175° (dec.; from methylenechloride/methanol/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand diphenylcarbamoyl-L-phenyl-alanine, an epimeric mixture of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-b4-isopropyl-5-hexenyl]-α-[[N-(diphenylcarbamoyl)-3-phenyl-L-alanyl]amino]imidazole-4-propionamideand(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[N-(diphenylcarbamoyl)-3-phenylD-alanyl]amino]imidazole-4-propionamide, in which the first-named epimerpredominates, melting point 106° (from methylene chloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand isobutoxycarbonyl-L-phenylalanine, the isobutyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamateas white crystals, melting point 147° (from ether/methylenechloride/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand D-pyroglutamic acid, the(S)-N-[(1S,2S,4S)-1-[cyclohexylmethyl]-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[[5-oxo-Dprolyl]amino]hydrocinnanamido]-imidazole-4-propionamide as a whitesolid, melting point 200° (dec.; from methanol/ethyl acetate/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand L-pyroglutamic acid, the(S)-N-[(1S,2S,4S)-1-[cyclohexylmethyl]-2-hydroxy-4-isopropyl5-hexenyl]-α-[(S)-α-[[5-oxo-L-prolyl]amino]hydrocinnamamido]-imidazole-4-propionamideas white crystals, melting point 148° (from methylenechloride/methanol/ether);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand N-t-butoxycarbonyl-α-methyl-L-alanine, the t-butyl[1-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazole-4-ylethyl]carbamoyl]phenethyl]-carbamoyl]-1-methylethyl]-carbamateas white crystals, melting point 112° (from methylenechloride/tetrahydrofuran/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamide and Fmoc-Ser(t-Bu)OH, the 9H-fluoren-9-yl[(S)-2-t-butoxy-1-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenethyl]carbamoyl]ethyl]carbamate as a white solid, melting point 180° (dec.; from methylenechloride/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand dibenzylsuberaneacetic acid, the(S)-N-[(1S,2S,4S)]-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[N-(9H-fluoren-9-ylacetyl)-3-phenyl-L-alanyl]amino]imidazole-4-propionamideas white crystals, melting point 119° (from methylenechloride/ether/hexane);

From N-[(1S,2S,4S)-1-(cyclohexylmethyl)2-hydroxy-4-isopropyl-5-hexenyl]-α-(3-phenyl-L-alanyl)imidazole-4-propionamideand adamantylacetic acid, the(S)-α-[[N-(1-adamantylacetyl)-3-phenyl-L-alanyl]amino]-N-[(1S,2S,4S)-1-[cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideas white crystals, melting point 120° (from methylenechloride/ether/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand phenyloxycarbonyl-L-phenylalanine, the benzyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate as white crystals, melting point 144° (from methylenechloride/ether);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 2,2,2-trichloroethoxycarbonyl-L-phenylalanine, the2,2,2-trichloroethyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenethyl]carbamate as white crystals, melting point 109° (from methylenechloride/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(3-phenyl-N-D-prolyl-L-alanyl)amino]imidazole-4-propionamideand 4-imidazolylpropionic acid, which in turn was prepared byhydrogenating urocanic acid, theN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[(R)-1-(3-imidazol-4-ylpropionyl]-2-pyrrolidinecarboxamido]hydrocinnamamido]imidazole-4-propionamidein the form of a foam, MS: 760 (M+H)⁺ ;

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand (R)-1-[(3-hydroxy-2-pyridyl)carbonyl]-2-pyrrolidinecarboxylic acid,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[(R)-1-[(3-hydroxy-2-pyridyl)carbonyl]-2-pyrrolidinecarboxamido]hydrocinnamamido]imidazole-4-propionamideas a white solid, melting point 198° (dec.; from methylenechloride/methanol/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand (R)-1-[(dibenzylacetyl)-2-pyrrolidinecarboxylic acid, the (S)-N[(1S,2S,4S)-1-(cyclohexylmethyl) 2-hydroxy-4-isopropyl-5-hexenyl]-α-[(S)-α-[(R)-1-(dibenzylacetyl)-2-pyrrolidinecarboxamido]hydrocinnamamido]imidazole-4-propionamideas white crystals, melting point 104° (from methylenechloride/ether/hexane);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 1-t-butoxycarbonylaminocyclohexanecarboxylic acid, the t-butyl1-[[(S)-α-[[(S)-1-[(1S,2S,4S)-1-(cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-cyclohexanecarbamate as a white solid, MS: 764 (M+H)⁺ ;

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(3-phenyl-N-D-prolyl-L-alanyl)amino]imidazole-4-propionamideand isovaleric acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[(R)-1-isovaleryl-2-pyrrolidinecarboxamido]hydrocinnamamido]imidazole-4-propionamideas a foam, MS: 721 (M+H)⁺ ;

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(D-prolylamino)hydrocinnamamido]imidazole-4-propionamidedihydrochloride and isovaleric acid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[(S)-α-[(1-isovaleryl-L-propyl)carbonyl]-3-phenyl-L-alanyl]amino]-imidazole-4-propionamideas a foam, MS: 719 (M+H)⁺.

TheN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(3-phenyl-N-D-prolyl-L-alanyl)amino]-imidazole-4-propionamideused as the starting material was prepared from the t-butyl(R)-2-[[(S)-α-[[(S)-1-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylatedescribed in Example 16 by cleaving off the t-butoxycarbonyl group withhydrogen chloride in dioxane in a manner analogous to that described inExample 8.

The acids used as starting materials are either known and availablecommercially or were prepared as follows:

Diphenylcarbamoyl-L-phenylalanine

Treatment of L-phenylalanine with diphenylcarbamoyl chloride indimethylformamide in the presence of triethylamine yielded, afterrecrystallization from methanol/methylene chloride/hexane, the desiredacid in the form of white crystals, melting point 167°.

Isobutoxycarbonyl-L-phenylalanine

Treatment of L-phenylalanine with isobutyl chloroformate in a manneranalogous to that described above, yielded yielded the desired acid asan oil [MS: 266 (M+H)⁺ ] which crystallized out upon standing and whichwas used directly in the next step.

Phenyloxycarbonyl-L-phenylalanine

In a manner analogous to that described above, by reactingL-phenylalanine and phenyl chloroformate there was obtained the desiredacid in the form of a foam [MS: 286 (M+H)⁺ ] which was used directly inthe next step.

2,2,2-Trichloroethoxycarbonyl-L-phenylalanine

L-phenylalanine was reacted with 2,2,2-trichloroethyl chloroformate in a2N sodium bicarbonate solution, and after the usual working-up there wasobtained the desired acid as crystals, melting point 126° (frommethylene chloride/hexane).

(R)-1-[(3-Hydroxy-2-pyridyl)carbonyl]-2-pyrrolidinecarboxylic acid

3-Hydroxypicolinic acid was condensed with D-proline benzyl ester in theusual manner and the ester obtained was thereafter convertedhydrogenolytically into the desired acid, which was used directly in thenext step.

(R)-1-(Dibenzylacetyl)-2-pyrrolidinecarboxylic acid

Dibenzylacetic acid was condensed with D-proline benzyl ester in theusual manner and the ester obtained was converted hydrogenolyticallyinto the desired acid, which was used directly in the next step.

1-t-Butoxycarbonylaminocyclohexanecarboxylic acid

1-Aminocyclohexanecarboxylic acid was converted with di-t-butyldicarbonate in the usual manner into the corresponding N-protected acid,which was used directly in the next step.

EXAMPLE 14

40 mg of 9H-fluoren-9-yl[(S)-2-t-butoxy-1-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]ethyl]carbamatewere dissolved in 5 ml of methylene chloride and 0.4 ml of piperidineand allowed to stand at room temperature for 2 hours. Thereafter, thereaction mixture was evaporated to dryness and the residue waschromatographed on silica gel with a 14:1:0.1 mixture of methylenechloride, methanol and ammonia. Recrystallization of the crude productyielded(S)-α-[[N-(3-t-butoxy-L-alanyl)-3-phenyl-L-alanyl]amino]-N-[(1S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-propionamideas a white solid, melting point 103° (dec.; from methylene chloride/ether/hexane).

EXAMPLE 15

t-Butyl[4[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]butyl]carbamate was dissolved in 0.3N methanolic hydrochloric acid and allowedto stand at room temperature for 18 hours. Thereafter, the reactionmixture was evaporated to dryness and the residue was chromatographed onsilica gel, with(S)-α-(5-aminovaleramido)-N-[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]hydrocinnamamidedihydro-chloride being obtained as a foam, MS: 637 (M+H)⁺.

In a manner analogous to that described above, but using 3.5N hydrogenchloride in acetic acid, from t-butyl(R)-2-[[(S)-α-[[(S)-1-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]2-imidazol-4-ylethyl]carbamoyl]-phenethyl]carbamoyl]-1-pyrrolidinecarboxylate,the preparation of which was described in Example 16, there was obtainedN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(3-phenyl-N-D-prolyl-L-alanyl)amino]-imidazole-4-propionamideas a thin-layer chromatographically uniform, hygroscopic solid, MS: 635(M+H)⁺.

EXAMPLE 16

The following compounds were prepared by hydrogenating the correspondingolefins in a manner analogous to that described in Example 2:

From ethyl3-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]acrylate,the ethyl[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-propionateas a thin-layer chromatographically uniform solid, MS: 668 (M+H)⁺ ;

From(S)-α-[[N-(1-adamantylacetyl)-3-phenyl-L-alanyl]amino]-N-[(1S,2S,4S)-1-[cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,the(S)-α-[(S)-α-[2-(1-adamantyl)acetamido]hydrocinnamamido]-N-[(1S,2S,4S)-1-cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]imidazole-4-propionamideas a 15 white solid, MS: 717 (M+H)⁺ ;

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(3-pyridineacetamido)hydrocinnamamido]imidazole-4-propionamide,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[2-(3-pyridyl)acetamido]hydrocinnamamido]-imidazole-4-propionamideas white crystals, melting point 211° (from methylenechloride/methanol/ether);

From(S)-N-[(1S,2S,4S)-1-[cyclohexylmethyl]-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.[(S)-α-[[5-oxo-L-prolyl]amino]hydrocinnamamido]imidazole-4-propionamide,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[(S)-5-oxo-2-pyrrolidinecarboxamido]hydrocinnamamido]imidazole-4-propionamideas a thin-layer chromatographically uniform solid, MS: 651 (M+H)⁺.

From the epimer mixture of(S)-N-[(1S,2S,4S)-1-[cyclohexylmethyl]-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[[5-oxo-D-prolyl]amino]-hydrocinnamamido]imidazole-4-propionamideand(S)-N-[(1S,2S,4S)]-1-[cyclohexylmethyl]-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[[5-oxo-L-prolyl]amino]hydrocinnamamido]imidazole-4-propionamide,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[(RS)-5-oxo-2-pyrrolidinecarboxamido]hydrocinnamamido]-imidazole-4-propionamideas a solid, MS: 651 (M+H)⁺ ;

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[N-(9H-fluoren-9-ylacetyl)-3-phenyl-L-alanyl]amino]-imidazole-4-propionamide,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[2-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)acetamido]hydrocinnamamido]-imidazole-4-propionamideas a thin-layer chromatographically uniform white solid, MS: 775 (M+H)⁺;

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[N-(diphenylcarbamoyl)-3-phenyl-D-alanyl]amino]imidazole-4-propionamide,the ethyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate as white crystals, melting point 196° (from methanol/methylenechloride/ether);

From benzyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmetehyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate, the phenyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy4-isopropylhexyl]carbamoyl]-2-imidazol- 4-ylethyl]carbamoyl]phenethyl]carbamate as white crystals, melting point 157° (from methylenechloride/methanol/ether);

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(4-nitrocinnamamido)hydrocinnamamido]imidazole-4-propionamide,the(S)-α-[(S)-α-(4-aminohydro-cinnamamido)hydrocinnamamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-imidazole-4-propionamideas white crystals, melting point 174° (from methylene chloride/methanol/ether);

From(2S,3S,5S)-2-(Boc-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol,the t-butyl(R)-2-[[(S)-α-[[(S)-1-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-2-imidazol4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylate aswhite crystals, melting point 173° (from methylenechloride/methanol/hexane);

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(4-oxavaleramido)hydrocinnamamido]imidazole-4-propionamide,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-4-oxovaleramido)hydrocinnamamido]imidazole-4-propionamideas a foam, MS: 638 (M+H)⁺ ;

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(4-hydroxyhydrocinnamamido)hydrocinnamamido]-imidazole-4-propionamide,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-(4-hydroxyhydrocinnamamido)hydrocinnamamido]imidazole-4-propionamideas a white solid, melting point 120° (dec.; from methylenechloride/ether/hexane);

From(S)-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(3-pyridineacrylamido)hydrocinnamamido]imidazole-4-propionamide,the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[3-(3-pyridyl)propionamido]hydrocinnamamido]-imidazole-4-propionamideas white crystals, melting point 195° (from methanol/ether/hexane);

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl[-.alpha.-[(S)-α-nicotinamidohydrocinnamamido]imidazole-4-propionamide,theN-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenethyl]nicotinamideas a white solid, melting point 112° (dec.; from methylenechloride/ether/hexane);

From(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(imidazol-4-acrylamido)hydrocinnamamido]imidazole-4-propionamide,theN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl]-α-[(S)-.alpha.-imidazole-4-propionamidohydrocinnamamido]-imidazole-4-propionamideas white crystals, melting point 118° (from methanol/ether/hexane);

From t-butyl[1-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]-1-methylethyl]carbamate, the t-butyl[1-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol4-ylethyl]-carbamoyl]hydrocinnamoyl]carbamoyl]-1-methylethyl] carbamateas a foam, MS; 725 (M+H)⁺.

EXAMPLE 17

A mixture of 95 mg (0.133 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(3-phenyl-N-D-prolyl-L-alanyl)amino]imidazole-4-propionamide,0.025 ml (0.199 mmol) of pivaloyl chloride and 0.185 ml (1.33 mmol) oftriethylamine in 10 ml of tetrahydrofuran was stirred at roomtemperature overnight. After the usual working-up and chromatographicpurification on silica gel with a 20:1:0.1 mixture of methylenechloride, methanol and ammonia, there was obtained(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(S)-α-[(R)-1-pivaloyl-2-piperidinecarboxamido]hydrocinnamamido]-imidazole-4-propionamideas a thin-layer chromatographically uniform solid, MS: 722 (M+H)⁺.

EXAMPLE 18

20 mg of(S)-α-[[N-(3-t-butoxy-L-alanyl)-3-phenyl-L-alanyl]amino]-N-[(1S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-propionamidewere dissolved in 1 ml of aqueous trifluoroacetic acid (95%) and stirredat room temperature for 2.5 hours. Evaporation of the reaction mixtureand chromatographic purification on silica gel with a 8:1:0.1 mixture ofmethylene chloride, methanol and ammonia yielded thin-layerchromatographically uniform(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[N-(L-serylamino)-3-phenyl-L-alanyl]amino]imidazole-4-propionamide,MS: 625 (M+H)⁺.

EXAMPLE 19

195 mg ofN-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanoyl]-N-methyl-L-histidine benzylester were hydrogenated in the presence of 25 mg of palladium-on-carbon(5%) for 2 hours and theN-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanoyl]-N-methyl-L-histidineobtained was reacted in the usual manner with(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol.Chromatographic purification of the crude product obtained on silica gelwith a 140:10:0.1 mixture of methylene chloride, methanol and ammoniayieldedN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-2-benzyl-N,5,5-trimethyl-4-oxohexanamido]imidazole-4-propionamideas a thin-layer chromatographically uniform substance, MS: 635 (M+H)⁺.

The less polar epimericN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-2-benzyl-N,5,5-trimethyl-4-oxohexanamido]imidazole-4-propionamide,MS: 635 (M+H)⁺, wis obtained as a byproduct.

The N-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanoyl]-N-methyl-L-histidinebenzyl ester used as the starting material was prepared by condensingN-(α-methyl)-L-histidine benzyl ester with2-(R)-benzyl-4-oxo-5,5,5-trimethylvaleric acid and was used directly inthe next step.

EXAMPLE 20

100 mg (0.164 mmol) of ethyl(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyratewere stirred at room temperature for 3 hours in a solution of 30%hydrazine hydrate in methanol. Thereafter, the reaction mixture wasevaporated and the residue was chromatographed on silica gel with a14:1:0.1 mixture of methylene chloride, methanol and ammonia.Crystallization of the crude product from methanol/methylenechloride/ether yielded(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]4-phenylbutyrohydrazideas white crystals, melting point 109°.

The ethyl(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrateused as the starting material was prepared as described in Example 40.

EXAMPLE 21

0.083 ml (0.54 mmol) of 4-piperidinecarboxylic acid ethyl ester wasreacted at room temperature with 210 mg (0.36 mmol) of ethyl1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-yl-ylethyl]carbamoyl]-4-phenylbutyryl]carboxylatein 20 ml of acetonitrile in the presence ofbis-(2-oxo-3-oxazolidinyl)phosphine chloride. After working-up in theusual manner and chromatography on silica gel, there was obtained ethyl1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-4-piperidinecarboxylateas a foam, MS: 720 (M+H)⁺.

The following compounds were prepared in a manner analogous to thatdescribed above:

From(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyricacid and L-prolinol, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[[(2-hydroxymethyl)-1-pyrrolidinyl]carbonyl]methyl]hydrocinnamamido]-imidazole-4-propionamideas a white solid, melting point 103° (dec.; from methylenechloride/ether/hexane);

From(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyricacid and N-methylethanolamine, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[[(2-hydroxyethyl)methylcarbamoyl]methyl]hydrocinnamamido]-imidazole-4-propionamideas a white solid, melting point 82° (dec.; from methylenechloride/ether/hexane);

From(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyricacid and N,N-dimethylethylenediamine, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[[[2-(dimethylamino)ethyl]carbamoyl]methyl]hydrocinnamamido]-imidazole-4-propionamideas a white solid, melting point 98° (from methylene chloride/hexane);

From(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyricacid and N,N-dimethylpropylenediamine, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[[[3-(dimethylamino)propyl]carbamoyl]methyl]hydrocinnamamido]-imidazole-4-propionamideas white crystals, melting point 98° (from methylene chloride/ether).

The (R)-3-[[(S)-1-[[(1S2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyricacid used as the starting material was prepared as follows:

100 mg (0.16 mmol) of ethyl(R)-3-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate(see Example 40) in 3 ml of ethanol were treated with 0.66 ml of 0.5N(0.33 mmol) sodium hydroxide solution and stirred at room temperaturefor 2.5 hours. The mixture was then neutralized with 0.33 ml (0.33 mmol)of 1N hydrochloric acid, ethyl acetate was added thereto and the mixturewas washed with saturated sodium chloride solution. The organic phasewas then dried over sodium sulfate and the solvent was removed underreduced pressure, to obtain 91 mg (95%) of(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]-4-phenylbutyric acid as an amorphous powder. MS:581 (M+H)⁺.

EXAMPLE 22

70 mg (0.1 mmol) of ethyl1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-4-piperidinecarboxylatewere suspended in 1N sodium hydroxide solution in a 9:1 mixture ofmethanol and water and stirred at room temperature for 3 hours.Thereafter, the solvent was evaporated and the residue wasrecrystallized from methanol/methylene chloride/hexane, to obtain1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-4-piperidinecarboxylicacid as white crystals, melting point 169°.

EXAMPLE 23

Reaction of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-(D-prolylamino)hydrocinnamamido]imidazole-4-propionamidedihydrochloride (see Example 8) with Fmoc-Ser(t-Bu)OH in manneranalogous to that described in Example 1, treatment of theFmoc-protected compound obtained with piperidine and subsequentchromatography of the crude product on silica gel with a 200:10:1mixture of methylene chloride, methanol and ammonia yielded thin-layerchromatographically pure(S)-α-[[N-[1-(3-butoxy-L-alanyl)-D-propyl]-3-phenyl-D-alanyl]amino]-N-[(2S,3S,4S)-3-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideas a foam, MS: 779 (M+H)⁺.

EXAMPLE 24

A mixture of 100 mg (0.17 mmol) of 2-t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenethyl]carbamate and 65 mg (0.25 mmol) of osmium tetroxide in 20 ml of pyridinewas stirred at room temperature overnight. Thereafter, 4 ml of 33%sodium bisulphite solution were added and the mixture was stirred for afurther hour. Chromatography of the crude product, obtained after theusual working-up, on 20 g of silica gel with a 9:1:0.1 mixture ofchloroform, methanol and ammonia yielded 65 mg of thin-layerchromatoqraphically uniform(2RS,3S,5S,6S)-6-(Boc-Phe-His-NH)-3-isopropyl-8-methyl-1,2,5-nonanetriol,MS: 632 (M+H)⁺.

EXAMPLE 25

A mixture of 411 mg (0.82 mmol) of(RS)-α-[[(S)-α-(Boc-Pro-NH)phenethyl]carbamoyl]imidazole-4-propionicacid, 200 mg (0.82 mmol) of(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol, 0.1 ml(0.82 mmol) of 4-ethylmorpholine ,222 mg (1.64 mmol) of HOBT and 203 mg(0.99 mmol) of DCC was dissolved in 20 ml of dimethylformamide andstirred at room temperature for 2 days. The separated precipitate wasfiltered off and the solvent was evaporated under reduced pressure.After the usual working-up, there were obtained 590 mg of a crudeproduct which was chromatographed on 30 g of silica gel with a 20:1:0.1mixture of methylene chloride, methanol and ammonia. Recrystallizationof the thin-layer chromatographically uniform product from methylenechloride/ether/hexane yielded 260 mg of t-butyl(S)-2-[[(S)-α-[(RS)-α-[[(1S,2S,4S)-1-(cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]imidazole-3-propionamido]-phenethyl]carbamoyl]-1-pyrrolidinecarboxylateas crystals, melting point 112°.

The(RS)-α-[[(S)-α-(Boc-Pro-NH)phenethyl]-carbamoyl]imidazole-4-propionicacid used as the starting material was prepared as follows:

10 8 g (30 mmol) of Boc-Pro-Phe-OH and 3.0 g (30 mmol) ofN-methylmorpholine were dissolved in 120 ml of tetrahydrofuran andcooled to -20°. 4.1 g of isobutyl chloroformate in 15 ml oftetrahydrofuran were added dropwise to this solution and after 5 minutesat -20° a solution of 3.9 g (60 mmol) of sodium azide in 30 ml of waterwas added dropwise. After completion of the addition, the mixture wasstirred at 0° for 30 minutes, then diluted with ice-cold ethyl acetateto double the volume, and the reaction mixture was subsequently treatedwith cold saturated sodium bicarbonate solution and then with coldsaturated sodium chloride solution. The organic phase separated, driedover magnesium sulphate and evaporated under reduced pressure at atemperature of 20°-25°. The residue was dissolved in 300 ml of tolueneunder a nitrogen atmosphere and heated to 80° . Then. 4.9 g (45 mmol,1.5 mol equivalents) of benzyl alcohol were added and the reactionmixture was heated to reflux for 6 hours. After cooling and evaporatingthe reaction solution, the residue was triturated with a 1:1 mixture ofether and hexane and the separated precipitate was filtered off. Afterdrying the filtrate under reduced pressure, there were obtained 11 g(79%) of [(R)-1-(Boc-Pro-NH)-1-(benzylamino)ethyl]- benzene, meltingpoint 155°-157°.

4.7 g (10 mmol) of the above compound in 300 ml of tetrahydrofuran werehydrogenated for 3 hours in the presence of 1.0 g of palladium-on-carbonat 343.25 kPa. After completion of the hydrogen uptake, the catalyst wasfiltered off and the filtrate was evaporated under reduced pressure. Theresidue was dissolved in 60 ml of dimethyl formamide and 1.98 g (10mmol) of (RS)-(imidazol-4-ylmethyl)malonic acid monomethyl ester⁴. Thesolution obtained was then cooled to 0° and treated with 3.0 g (20 mmol)of HOBT and 2.2 g (12 mmol) of EDC. The reaction mixture was then leftto warm to room temperature and stirred at this temperature for 48hours. After evaporating the reaction mixture in a high vacuum, theresidue was dissolved in ethyl acetate, washed with water andsubsequently extracted with 1N citric acid. The citric acid extract wasneutralized with sodium bicarbonate and extracted with ethyl acetate.The organic extract was then dried over sodium sulfate and evaporatedunder reduced pressure. Chromatography of the residue on silica gel andrecrystallization of the crude product obtained from ethyl acetate/etheryielded 2.5 g (49%) of(RS)-α-[[(S)-α-(Boc-Pro-NH)-phenethyl]carbamoyl]-imidazole-4-propionicacid methyl ester, melting point 142°-143°.

1.54 g (3 mmol) of the above ester were dissolved in 6 ml of ethanol andtreated with 3.15 ml (3.15 mmol, 1.05 mol equivalents) of 1N sodiumhydroxide solution. After stirring for 3 hours while cooling with ice,3.15 ml (3.15 mmol) of 1N H₂ SO₄ were added and the reaction mixture wasevaporated under reduced pressure. The residue was triturated with 300ml of ethanol and the insoluble sodium sulfate was filtered off.Concentration of the ethanolic solution yielded 1.47 g (98%) of(RS)-α-[[(S)-α-(Boc-Pro-NH)phenethyl]carbamoyl]imidazole-4-propionicacid, melting point 120° (dec.).

EXAMPLE 26

A mixture of 1.05 g (2.06 mmol) of Boc-Phe^(R) His(Bom)-OH, 0.5 g (2.06mmol) of(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol. 0.26ml (2.06 mmol) of 4-ethylmorpholine, 0.56 g (4.12 mmol) of HOBT and 0.51g (2.47 mmol) of DCC in 40 ml of dimethylformamide was stirred at roomtemperature overnight. Separated urea was then filtered off and thesolvent was evaporated under reduced pressure. Working-up of the residuein the usual manner yielded 1.69 g of t-butyl[(S)-1-benzyl-2-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]amino]ethyl]carbamate,which was used directly in the next step.

1.69 g (about 2.06 mmol) of t-butyl[(S)-1-benzyl-2-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-4-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]amino]-ethyl]carbamate were hydrogenated at room temperature overnight in thepresence of 0.5 g of palladium-on-carbon (5%) in 50 ml of a 4:1 mixtureof acetic acid and water and 0.8 g of N,N'-dimethylethylenediamine.After completion of the hydrogen uptake, the catalyst was filtered offand the filtrate was evaporated and treated twice in succession withtoluene and then again evaporated to dryness. Chromatography of theresidue on 180 g of silica gel with a 20:1:0.1 mixture of methylenechloride, methanol and ammonia as the eluting agent yielded 1.13 g of acrude product which was recrystallized from methylenechloride/ether/hexane, to obtain 730 mg of t-butyl[(S)-1-benzyl-2-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]amino]ethyl]carbamate as crystals, melting point 144°.

The Boc-phe^(R) His(Bom)OH, used as the starting material was preparedas follows:

58 g of Boc-Phe-His(Bom)OMe, which was prepared by coupling Boc-Phe-OHwith His(Bom)OMe according to usual methods. 30.35 g of Lawesson reagentand 700 ml of benzene were heated to reflux overnight. Thereafter, thereaction mixture was cooled and evaporated to dryness. The residue wasthen filtered through 1.5 g of silica gel, first with methylene chlorideand then with methylene chloride, with the progressive addition ofethanol (up to 7%). There were thus obtained 35.56 g of[(S)-2-(Boc-NH)-3-phenylthiopropionyl]His(Bom)OMe in the form of a foam,MS: 553 (M+H)⁺.

0.5 g of the above thio compound and 5 g of Raney-nickel in 30 ml ofethanol were stirred in a hydrogen atmosphere for 2 hours. The catalystwas then filtered off and the filtrate was evaporated. Chromatography ofthe crude product on 30 g of silica gel with chloroform, a 98:2 mixtureof chloroform and ethanol and a 95:5 mixture of chloroform and ethanolas the eluting agent yielded 0.24 g of[(S)-2-(Boc-NH)-3-phenylpropyl]His(Bom)OMe in the form of a foam, MS;523 (M+H)⁺.

170 mg of the above ester in 2 ml of 1N sodium hydroxide solution in a1:1 mixture of methanol and water were stirred at room temperatureovernight. 1 ml of conc. acetic acid was then added and the reactionmixture was evaporated under reduced pressure. The residue was warmedthree times with 150 ml of methanol each time and decanted off. Themethanolic phase was evaporated and the residue was chromatographed on30 g of silica gel with a 4:1:1 mixture of butanol, acetic acid andwater, to obtain 100 mg of [(S)-2-(Boc-NH)-3-phenylpropyl]-His(Bom)OH inform of a foam, MS: 509 (M+H)⁺.

EXAMPLE 27

0.17 g (0.56 mmol) of 2-(RS)-benzyl-4-(4-chlorophenyl)-4-oxo-butyricacid was dissolved in 10 ml of dimethylformamide and treated with 0.20 g(0.51 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,0.057 g (0.56 mmol) of triethylamine and 0.21 g (0.56 mmol) of HBTU andstirred at room temperature overnight. The mixture was subsequentlyevaporated in a high vacuum. The residue was dissolved in ethyl acetateand then washed with saturated sodium bicarbonate solution and saturatedsodium chloride solution. After drying the organic phase over sodiumsulfate, the solvent was evaporated under reduced pressure and theresidue, for purification, was chromatographed on silica gel using a95:5 mixture of methylene chloride and methanol which contained 0.5%ammonium hydroxide. There were obtained 270 mg (78%) of(S)-α-[(RS)-α-(4-chlorophenylacetyl)hydrocinnamamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidein the form of a yellowish foam. MS: 675 (M⁺).

The 2-(RS)-benzyl-4-(4-chlorophenyl)-4-oxo-butyric acid used as thestarting material was prepared as follows:

5.0 g (20 mmol) of benzylmalonic acid diethyl ester were added dropwiseat room temperature to a suspension of 0.87 g of sodium hydridedispersion (55% in oil) in 20 ml of dimethylformamide. Subsequently, thereaction mixture was stirred at room temperature for 20 minutes andthereafter 4.67 g (20 mmol) of omega-bromo-4-chloroacetophenone in 25 mlof dimethylformamide were added dropwise. After completion of theaddition, the deep brown colored reaction mixture was stirred at roomtemperature overnight and thereafter evaporated in a high vacuum. Theresidue was dissolved in methylene chloride, washed with water and driedover sodium sulfate. Thereafter, the solvent was evaporated underreduced pressure and the residue, for purification, was chromatographedon silica gel with a 6:1 mixture of hexane and ether, to obtain 5.17 g(64%) of 2-(RS)-benzyl-2-carbethoxy-4-(4-chloro-phenyl)-4-oxobutyricacid as a yellowish solid. MS: 357 (M-OC₂ H₅)⁺, 311 (M-benzyl)⁺.

6.15 ml (3 mol equivalents) of 2N sodium hydroxide solution were addedto a solution of 1.64 g (4.1 mmol) of the above-named ethyl ester in 10ml of ethanol and 9 ml of water, and the reaction mixture was stirred atroom temperature for 16 hours. The mixture was subsequently adjusted topH 3 with 1N hydrochloric acid and extracted with methylene chloride.The organic phase was dried over sodium sulfate, evaporated underreduced pressure and the crystalline residue was heated to 150°-160°until CO₂ evolution had terminated. After cooling, the residue wasdissolved in ether and brought to crystallization by the addition ofhexane. There was thus obtained 970 mg (79%) of2-(RS)-benzyl-4-(4-chlorophenyl)-4-oxobutyric acid as yellowishcrystals, melting point 137°-138°.

EXAMPLE 28

1.57 g (4.03 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,0.45 g (4.43 mmol) of triethylamine and 1.68 g (4.43 mmol) of HBTU wereadded to a solution of 1.45 g (4.43 mmol) of2-(RS)-(1-naphthylmethyl)-3-morpholinocarbonylpropionic acid⁵ in 60 mlof dimethylformamide. The yellow reaction solution obtained was thenstirred at room temperature for 15 hours and subsequently evaporated ina high vacuum. The residue was dissolved in 150 ml of methylenechloride, the organic phase was washed twice with 30 ml of saturatedsodium bicarbonate solution and 30 ml of water, dried over sodiumsulfate and evaporated under reduced pressure. For purification andseparation of the two epimers, the residue was chromatographed on silicagel with a 95:5 mixture of methylene chloride and methanol whichcontained 0.5% ammonium hydroxide. There was thus obtained 855 mg (30%)of an isomer with the Rf value 0.45 and 726 mg (26%) of an isomer withthe Rf value 0.33. Both isomers exhibited the same mass spectrum, MS:700 (M+H)⁺.

The 2-(RS)-(1-naphthylmethyl)-3-morpholinocarbonylpropionic acid used asthe starting material was prepared as follows:

1.10 g (12.6 mmol) of morpholine, 2.42 g (12.6 mmol) of EDC and 3.43 g(25.2 mmol) of HOBT were added to a solution of 3.63 g (12.6 mmol) of3-ethoxycarbonyl-4-(1-naphthyl)butyric acid⁶ in 50 ml ofdimethylformamide, and the reaction solution was stirred at roomtemperature for 15 hours and subsequently evaporated in a high vacuum.The residue was dissolved in ethyl acetate and the organic phase waswashed with water, saturated sodium bicarbonate solution and saturatedsodium chloride solution, dried over sodium sulfate and evaporated underreduced pressure. The residue was chromatographed on silica gel with a98:2 mixture of methylene chloride and ethanol, to obtain 3.78 g (84%)of 2-(RS)-(1-naphthylmethyl)-3-morpholinocarbonylpropionic acid ethylester as a yellowish oil which began to crystallize out after lengthystanding. MS: 355 (M⁺).

1.7 g (4.78 mmol) of the above-named ethyl ester were dissolved in 6 mlof ethanol and, after the addition of 7.2 ml (7.2 mmol) of 1N sodiumhydroxide solution, stirred at 50° for 3 hours. After cooling, 7.5 ml(7.5 mmol) of 1N hydrochloric acid were added to the deep yellowreaction solution and the mixture was subsequently evaporated underreduced pressure. The residue was dissolved in 100 ml of methylenechloride and the organic phase was washed twice with 20 ml of water,dried over sodium sulfate and evaporated under reduced pressure, toobtain 1.45 g (92%) of2-(RS)-(1-naphthylmethyl)-3-morpholinocarbonylpropionic acid as a yellowfoam which was used directly in the next step. MS: 327 (M⁺).

EXAMPLE 29

109 mg (0.38 mmol) of 3-(RS)-(1-naphthylmethyl)succinic acid 1-ethylester were dissolved in 6 ml of acetonitrile and 1 ml ofdimethylformamide and, after the addition of 135 mg (0.35 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,39 mg (0.38 mmol) of triethylamine and 144 mg (0.38 mmol) of HBTU,stirred at room temperature for 6 hours. Subsequently, the reactionsolution was evaporated in a high vacuum and the residue was dissolvedin 50 ml of ethyl acetate and washed 3 times with 10 ml of saturatedsodium bicarbonate solution. The organic phase was dried over sodiumsulfate and evaporated under reduced pressure, and the residue waschromatographed on silica gel with a 95:5 mixture of methylene chlorideand methanol which contained 0.1% ammonium hydroxide, to obtain 103 mg(45%) of (RS)-β-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]-1-naphthylbutyricacid ethyl ester as a yellowish foam. MS: 594 (M-ethanol-water)⁺

The 3-(RS)-(1-naphthylmethyl)succinic acid 1-ethyl ester used as thestarting material was prepared as follows:

820 mg (3.44 mmol) of 2-(1-naphthylmethylene)succinic acid anhydride⁶were heated to reflux for 4 hours in 5 ml of ethanol. Subsequently, thereaction mixture was evaporated under reduced pressure, the residue wastaken up in 10 ml of saturated sodium bicarbonate solution and extractedwith ether. The aqueous phase was acidified with 1N hydrochloric acidand extracted with ether. After drying the ether extract over sodiumsulfate and evaporation under reduced pressure, there remained 710 mg(73%) of 3-(RS)-(1-naphthylmethylene)succinic acid 1-ethyl ester.

These 710 mg (2.5 mmol) of ethyl ester were dissolved in 5 ml of ethanoland hydrogenated for 15 hours in the presence of 100 mg ofpalladium-on-carbon. Thereafter, the catalyst was filtered off, thefiltrate was evaporated under reduced pressure and the residue waschromatographed on silica gel with a 98:2 mixture of methylene chlorideand methanol, to obtain 190 mg (27%) of3-(RS)-(1-naphthylmethyl)succinic acid 1-ethyl ester. MS: 286 (M)⁺

EXAMPLE 30

In a manner analogous to that described in Example 27, by condensing(αRS,S)-α-benzyl-1-t-butoxycarbonyl-γ-oxo-2-pyrrolidinebutyric acid with(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand subsequent epimer separation by chromatography, there were obtainedt-butyl(S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate(less polar isomer) and t-butyl(S)-2-[[(R)-γ-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate.MS: 734 (M+H)⁺

The (αRS,S)-α-benzyl-1-t-butoxycarbonyl-γ-oxo-2-pyrrolidinebutyric acidused as the starting material was obtained fromN-t-butoxycarbonyl-prolyl-bromomethane⁷ and benzylmalonic acid diethylester in analogy to the preparation of2-(RS)-benzyl-4-(4-chlorophenyl)-4-oxobutyric acid (see Example 27), MS:362 (M+H)⁺.

EXAMPLE 31

In a manner analogous to that described in Example 2, by catalyticallyhydrogenating t-butyl(S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]-phenethyl]acetyl]-1-pyrrolidinecarboxylateand t-butyl(S)-2-[[(R)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate,there was obtained t-butyl(S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate(less polar isomer) and t-butyl(S)-2-[[(R)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]-acetyl]-1-pyrrolidinecarboxylate.MS: 736 (M+H)⁺

EXAMPLE 32

In a manner analogous to that described in Example 1,1-[1-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]2-imidazol-4-yl-ethyl]-carbamoyl]-4-phenybutyryl]-D-prolyl]-L-prolinebenzyl ester was prepared as a mixture of 2 epimers by condensing(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]imidazole-4-propionamidewith(αRS,2R)-α-benzyl-2-[[(S)-2-[(benzyloxy)carbonyl]-1-pyrrolidinyl]carbonyl]-γ-oxo-1-pyrrolidinebutyricacid. MS: 867 (M+H)⁺

The acid used as the starting material was prepared as follows:

2-Benzyl-3-methoxycarbonylpropionic acid t-butyl ester, MS: 222 (M-C₄H₈)⁺, was prepared starting from 2-benzyl-3-methoxycarbonylpropionicacid⁸ according to the procedure described by U. Widmer in Synthesis1983, page 135.

415 mg of the above t-butyl ester were dissolved in 3 ml of t-butylalcohol and stirred at room temperature for 3 hours in the presence of1.5 ml of 1N sodium hydroxide solution. The reaction solution was thenevaporated under reduced pressure and the residue was dissolved in waterand washed with ether. The aqueous phase was thereafter neutralized with1.5 ml of 1N hydrochloric acid and extracted with methylene chloride.The organic extracts were dried over sodium sulfate and evaporated underreduced pressure, to obtain 2-benzyl-3-carboxypropionic acid t-butylester as a colorless oil, MS: 208 (M-C₄ H₈)⁺.

370 mg (1.4 mmol) of the above-named half ester, 409 mg (1.2 mmol) ofH-D-Pro-Pro-OBz and 270 mg (2 mol equivalents) of triethylamine weredissolved in 8 ml of dimethylformamide. 530 mg (1.4 mmol) of HBTU wereadded to this solution and the reaction mixture was stirred at roomtemperature for 15 hours and subsequently evaporated to dryness in ahigh vacuum. The residue was dissolved in ethyl acetate and washed withsaturated sodium bicarbonate solution. The organic phase was dried oversodium sulfate and evaporated under reduced pressure. Chromatography ofthe residue on silica gel with a 98:2 mixture of methylene chloride andmethanol yielded(αRS,2R)-α-benzyl-2-[[(S)-2-[(benzyloxy)carbonyl]-1-pyrrolidinyl]carbonyl]-γ-oxo-1-pyrrolidinebutyric acid t-butyl ester as a colorless foam. MS: 549(M+H)⁺.

505 mg (0.9 mmol) of the above t-butyl ester were stirred at roomtemperature for 3 hours in 10 ml of 2N hydrochloric acid/acetic acid.Thereafter, the reaction mixture was evaporated under reduced pressure,to obtain(αRS,2R)-α-benzyl-2-[[(S)-2-[(benzyloxy)carbonyl]-1-pyrrolidinyl]carbonyl]-γ-oxo-1-pyrrolidinebutyricacid as a colorless foam. MS: 493 (M+H)⁺.

The(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]imidazole-4-propionamideused as the starting material was prepared as follows:

50 mg of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidewere dissolved in 3 ml of methanol and hydrogenated at room temperaturefor 3 hours at normal pressure in the presence of 7 mg ofpalladium-on-carbon. Thereafter, the catalyst was filtered off andrinsed with methanol. The alcoholic solution was then evaporated underreduced pressure, to obtain(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]imidazole-4-propionamideas a colorless foam. MS: 393 (M+H)⁺.

EXAMPLE 33

The following compounds were prepared in a manner analogous to thatdescribed in Example 1:

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand (αRS,2R)-α-benzyl-2-[[(S)-2-[(benzyloxy)carbonyl]-1-pyrrolidinyl]-carbonyl]-γ-oxo-1-pyrrolidinebutyricacid, the1-[1-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-D-prolyl]-L-prolinebenzyl ester as a 1:1 epimer mixture, MS: 865 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideandN-(t-butoxycarbonyl)-N-[2-[(RS)-3-carboxy-4-phenylbutyramido]ethyl]glycinet-butyl ester, the two epimeric compounds t-butoxycarbonyl [2-[(R andS)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyramido]ethyl]-glycinet-butyl ester, MS: 837 (M+H)⁺ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand(R)-α-[[[2-hydroxy-1-(hydroxymethyl)-1-methyl]carbamoyl]methyl]hydrocinnamicacid, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]carbamoyl]methyl]hydrocinnamamido]imidazole-4-propionamide,MS: 668 (M+H)³⁰ ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 5-[(RS)-3-carboxy-4-phenylbutyramido]valeric acid t-butyl ester, thet-butyl5-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyramido]valerate,MS: 736 (M+H)⁺ ;

From (S)-α-amino-N-[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy 4-isopropyl5-hexenyl]imidazole-4-propionamide and 3-carboxy-4-phenylbutyrylL-proline t-butyl ester, the1-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-L-prolinet-butyl ester, MS: 734 (M+H)⁺ ;

From (S)-α-amino-N[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand (RS) 2-benzylmalonic acid monomethyl ester⁹, the methyl(RS)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]hydrocinnamateas a 1:1 mixture of the two epimers, MS: 580 (M⁺);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]imidazole-4-propionamide and 3-(RS)-ethoxycarbonyl-4-(1-naphthyl)butyric acid⁶, the ethyl(RS)-α-[[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]methyl]-1-naphthalenepropionate as a 1:1 mixture of the two epimers, MS 659(M+H)⁺ : ≢⁶ EPA 0.181.110

From(S)-α-amino-N-[(1S,2S,4S)-1-(Cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideand 2-(RS)-benzyl-3-morpholinocarbonylpropionic acid and subsequentchromatographic separation of the two epimers, the less polar(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[(morpholinocarbonyl)methyl]hydrocinnamamido]-imidazole-4-propionamide,MS: 650 (M+H)⁺, and the more polar(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[(morpholinocarbonyl)methyl]-hydrocinnamamido]-imidazole-4-propionamide,MS: 650 (M+H)³⁰ .

The acids used as starting materials were prepared as follows:

N-(t-Butoxycarbonyl)-N-[2-(RS)-3-carboxy-4-phenyl-butyramidoethyl]glycinet-butyl ester

0.84 g (2.4 mmol) ofN-(t-butoxycarbonyl)-N-(2-benzyloxycarbonylaminoethy)glycine¹⁰ wassuspended in 5 ml of toluene and heated to 80°. To the clear solutionobtained in this matter there were added, dropwise within 20 minutes,1.96 g of N,N-dimethylformamide di-t-butyl acetal. After completion ofthe addition, the reaction mixture was stirred at 80° for 30 minutes,then cooled and washed in succession with water, saturated sodiumbicarbonate solution and saturated sodium chloride solution. The organicphase was then dried over sodium sulfate and evaporated under reducedpressure, to obtainN-(t-butoxy-carbonyl)-N-(2-benzyloxycarbonlaminoethyl)glycine t-butylester as a colorless oil, MS: 409 (M+H)³⁰ . ¹⁰ U.S. Pat. No.Specification 4,145,337

0.78 g (1.9 mmol) ofN-(t-butoxycarbonyl)-N-(2-benzyloxycarbonylaminoethyl)glycine t-butylester was dissolved in 20 ml of methanol and hydrogenated at pH 4.5 inthe presence of 0.1 g of palladium-on-carbon. The pH value was heldconstant by means of methanol/hydrochloric acid. After completion of thehydrogen uptake, the catalyst was filtered off, the filtrate wasevaporated and the residue was dissolved in methylene chloride andwashed with saturated sodium carbonate solution. After drying theorganic phase over sodium sulfate and evaporation under reducedpressure, N-(t-butoxycarbonyl)-2-(2-aminoethyl)glycine t-butyl ester wasobtained in the form of an oil. NMR (250 MHZ, TMS, CDCL₃): δ1.44, 1.47(2xs,18H) 2.83 (s,2H) 3.36 (s,2H), 3.79, 3.87 (2Xs,2H).

Condensation of 3-ethoxycarbonyl-4-phenylbutyric acid withN-(t-butoxycarbonyl)-2-(2-aminoethyl)glycine t-butyl ester yieldedN-(t-butoxycarbonyl)-N-[2-[(RS)-3-(ethoxycarbonyl)-4-phenylbutyramido]ethyl]glycinet-butyl ester [MS: 492 (M)⁺ ] which, in turn, was hydrolyzed with 1Nsodium hydroxide solution in ethanol at 50° to give the desired acid,N-(t-butoxycarbonyl)-N-[2-[(RS)-3-carboxy-4-phenylbutyramido]ethyl]glycinet-butyl ester, MS: 408 (M-C₄ H₈)⁺.

(R)-α-[[[2-Hydroxy-1-(hydroxymethyl)-1-methyl]carbamoyl]methyl]hydrocinnamicacid

3-Ethoxycarbonyl-4-phenylbutyric acid ¹¹ and2-amino-2-methyl-1,3,-propanediol were condensed at room temperature inthe presence of EDC and HOBT in dimethylformamide, to obtain (RS-α-[[[2--hydroxy-1-(hydroxymethyl)-1-methyl]carbamoyl]methyl]hydrocinnamic acidethyl ester, MS: 324 (M+H)⁺.

50 mg of α-chymotrypsin were added to a suspension of 0.54 g (1.67 mmol)of(RS)-α-[[[2-hydroxy-1-(hydroxymethyl)-1-methyl]carbamoyl]methyl]hydrocinnamicacid ethyl ester in 15 ml of water. The pH value was held at 7.1 byadding 0.1N sodium hydroxide solution (temperature 25°). After 18 hours,9 ml of 0.1N sodium hydroxide solution had been consumed and thereaction mixture was extracted with ether. The aqueous phase wasadjusted to pH 4 with 1N hydrochloric acid and subsequently evaporatedunder reduced pressure. The residue was digested with ethyl acetate. Theorganic phase was evaporated under reduced pressure and the residue wasflash chromatographed on silica gel with a 9:1 mixture of methylenechloride and methanol, to obtain(R)-α-[[[2-hydroxy-1-(hydroxymethyl)-1-methyl]carbamoyl]methyl]hydrocinnamicacid as a colorless foam, MS: 264 (M-CH₂ OH)³⁰ .

5-[(RS)-3-Carboxy-4-phenylbutyramido]valeric acid t-butyl ester

3-Ethoxycarbonyl-4-phenylbutyric acid and 5-aminovaleric acid t-butylester¹² were condensed in the presence of EDC and HOBT indimethylformamide to give5-[(RS)-3-(ethoxycarbonyl)-4-phenylbutyramido]valeric acid t-butylester, MS: 392 (M+H)⁺. Saponification of this ester with 1N sodiumhydroxide solution in ethanol at 50° yielded5-[(RS)-3-carboxy-4-phenylbutyramido]valeric acid t-butyl ester, MS: 307(M-C₄ H₈)⁺.

3-Carboxy-4-phenybutyryl-L-proline t-butyl ester

The compound 3-carboxy-4-phenylbutyryl-L-proline t-butyl ester [MS: 361(M)^(+]) was synthesized by condensing 3-ethoxy-carbonyl-4-phenylbutyricacid and L-proline t-butyl ester to give3-ethoxycarbonyl-4-phenylbutyryl-L-proline t-butyl ester [MS: 389 (M)⁺ ]and subsequently saponifying analogously to the preparation of2-(RS)-benzyl-3-morpholinocarbonylpropionic acid described hereinafter.

(RS)-[(4-Benzyl-4-piperidinyl)carbamoyl ]imidazole -4-propionic acid

2 g (10 mmol) of (RS)-(imidazol-4-ylmethyl)malonic acid monomethyl ester(prepared according to a generally known procedure from malonic acidmethyl ester by alkylation with chloromethylimidazole and subsequentsaponification) and 1.91 g (10 mmol) of 4-amino-benzylpiperidine werestirred at room temperature for 72 hours with 1.91 g (10 mmol) of EDC in100 ml of dimethylformamide. The reaction solution was then evaporatedunder reduced pressure and the residue was dissolved in 100 ml ofmethylene chloride and washed with 30 ml of water. The organic phase wasthen dried over sodium sulfate and evaporated to dryness. The residuewas digested with ether and thereafter filtered off, to give(RS)-[(4-benzyl-4-piperidinyl)carbamoyl]imidazole-4-propionic acidmethyl ester as a colorless powder, MS: 370 (M)⁺.

371 mg (1 mmol) of the above methyl ester were dissolved in 10 ml of a1:1 mixture of methanol and water and stirred at room temperature for 24hours with 1 ml of 1N potassium hydroxide in methanol. The reactionsolution was then evaporated under reduced pressure, the residue wasdissolved in water and washed with ether. The aqueous phase was thenacidified with 1 mol equivalent of hydrochloric acid and evaporatedunder reduced pressure, to obtain(RS)-[(4-benzyl-4-piperidinyl)carbamoyl]imidazole-4-propionic acid as acolorless oil ⁺. MS: 312 (M-CO₂) .

2-(RS)-Benzyl-3-morpholinocarbonylpropionic acid

1.0 g (4.2 mmol) of 3-ethoxycarbonyl-4-phenylbutyric acid was dissolvedin 25 ml of dimethylformamide and treated with 0.37 g (4.2 mmol) ofmorpholine, 0.81 g (4.2 mmol) of EDC and 1.3 g (8.4 mmol) of HOBT andstirred at room temperature for 48 hours. The reaction solution was thenevaporated in a high vacuum and the residue was dissolved in ethylacetate and washed in succession with water, saturated sodiumbicarbonate solution and saturated sodium chloride solution. The organicphase was then dried over sodium sulfate and evaporated under reducedpressure, and the residue was chromatographed on silica gel using a 95:5mixture of methylene chloride and ethanol, to give2-(RS)-1-benzyl-3-morpholinocarbonylpropionic acid ethyl ester as acolorless oil, MS: 305 (M)⁺.

0.42 g (1.4 mmol) of the above ester was dissolved in 2 ml of ethanoland treated with 2.1 ml (1.5 mol equivalents) of 1N sodium hydroxidesolution. The reaction solution was then stirred at 50° for 4 hours andthe residue was dissolved in water and washed with ether. The aqueousphase was acidified with 2.3 ml of 1N hydrochloric acid and extractedwith methylene chloride. The organic extracts were dried over sodiumsulfate and evaporated under reduced pressure to give2-(RS)-benzyl-3-morpholinocarbonylpropionic acid was obtained as acolorless oil, which was used directly in the next step. MS: 277 (M)⁺.

Example 34

100 mg (0.13 mmol) of t-butoxycarbonyl[2-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2 imidazol-4-ylethyl]carbamoyl]-4-phenylbutyramido]ethyl]glycine t-butylester were dissolved in 2 ml of acetic acid and stirred at roomtemperature for 3 hours with 4 ml of 1N hydrochloric acid/acetic acid.Thereafter, the reaction mixture was evaporated under reduced pressureand the residue was digested with ether and filtered off, to giveN-[2-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol4-ylethyl]carbamoyl]-4-phenylbutyramido]ethyl]glycine dihydro chlorideas a powder, MS: 681 (M+H)⁺.

EXAMPLE 35

54 mg of I-butyl5-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5hexenyl]carbamoyl]2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyramido]valerate were dissolved in 1 ml of acetic acid and treated atroom temperature with 2 ml of hydrochloric acid/acetic acid (1.5N) andstirred at this temperature for 2.5 hours. The reaction mixture was thenevaporated under reduced pressure and the residue was digested withether and filtered off, to obtain5-[(RS)-3-[[(S)-1-2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyramido]valericacid hydrochloride as a colorless powder MS; 680 (M+H)⁺.

Example 36

The following compounds were prepared in a manner analogous to thatdescribed in Example 27:

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy.4-isopropyl-5-hexenyl]imidazole-4-propionamideand (RS) 2-benzyl-6,6-dimethyl-4-oxoheptanoic acid,, the(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(RS)-α-(4,4-dimethyl-2-oxopentyl)hydrocinnamamido]imidazole-4-propionamide,MS: 635 (M+H)⁺. ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]imidazole-4-propionamide and(RS)-α-benzyl-γ-oxocyclohexanebutyric acid and subsequent separation ofthe two epimers, the less polar(S)-α-[(S)-α-[(cyclohexylcarbonyl)methyl]hydrocinnamamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenylimidazole4-propionamide [MS 647 (M+H)⁺ ] and the more polar(S)-α-[(R)-α-[(cyclohexylcarbonyl)methyl]hydrocinnamamido]-N[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole4-propionamide, MS: 647 (M+H)⁺ ;

From (S)-α-amino-N-[(1S,2S,4S)1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]imidazole-4-propionamide and(RS)-α-benzyl-γ-oxocyclopentanebutanoic acid, the(S)-N-1(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(RS-α-[(cyclopentylcarbonyl)methyl]hydrocinnamamido]imidazole-4-propionamide,MS: 633 (M+H)⁺. :

From(S)-α-amino-N-(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand (RS)-2-benzyl 5,5-dimethyl-4-oxohexanoic acid, the(S)-α-[(RS)-2-benzyl-5,5-dimethyl-4-oxohexananamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,MS: 621 (M+H)⁺. ;

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand (R)-2-benzyl-5,5-dimethyl4-oxohexanoic acid, the(S)-α-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanamido]-N[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,MS; 621 (M+H)⁺. ;

From(S)-β-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5hexenyl]imidazole-4-propionamide and(αRS,S)-α-benzyl-1-(benzyloxycarbonyl)-γ-oxo-2-pyrrolidinebutyric acid,the benzyl (S)-2 [[(RS)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)2-hydroxy4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate,MS: 768 (M+H)⁺.

The acids used as the starting materials were prepared as follows inanalogy to the preparation of 2-(RS)benzyl-4-(4-chlorophenyl)-4-oxobutyric acid (see Example 27):

From 1 chloro-4,4-dimethyl 2-pentanone, which in turn was prepared in aknown manner from 3,3-dimethylbutyryl chloride by reaction withdiazomethane and hydrogen chloride, and benzyl malonic acid diethylether, the (RS)-2-benzyl-6,6 dimethyl-4-oxoheptanoic acid;

From bromoacetylcyclohexane¹³ and benzylmalonic acid diethyl ester, the(RS) β-benzyl-γ-oxo cyclohexaneburyrlo acid;

From bromoacetylcyclopentane¹³ and benzylmalonic acid diethyl ester, the(RS)-α- benzyl-γ-oxocyclopentanebutyric acid;

From N-benzyloxycarbonyl-prolyl-bromomethane which was prepared inanalogy to the preparation of N-t-butoxycarbonyl prolyl bromomethane¹⁴.and benzylmalonic acid diethyl ester, the(αRS,S)-α-benzyl-1-(benzyloxcarbonyl)-γ-oxo-2-pyrrolidinebutyric acid.

The (RS)-2-benzyl-5,5-dimethyl-4-oxohexanoic acid and the enantiomeric(R)-2-benzyl-5,5-dimethyl-4-oxohexanoic acid which were likewise used asstarting materials were known from European Patent Publication 0 184550.

EXAMPLE 37

The following compounds were prepared by catalytically hydrogenating thecorresponding olefins in a manner analogous to that described in Example2:

(S)-N-[(1S,2S,4S)-1-(Cyclohexylmethyl) 4-ethyl2-hydroxy-5-methylhexyl]-α-[(R)-α-[(morpholinocarbonyl)-methyl]hydrocinnamamido]imidazole-4-propionamide,MS: 652 (M+H)⁺ ;

(S)-N-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydro cinnamamido]-N-[(1S,2S,4S)-1(cyclohexylmethyl) 2-hydroxy-4-isopropylhexyl]imidazole 4-propionamide,MS: 623 (M+H)⁺ ;

(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)2-hydroxy-4-isopropylhexyl]-α-[[[[(R)-α-2-hydroxy-1-(hydroxymethyl)-1-methylethyl]carbamoyl]methyl]hydrocinnamamido]imidazole-4-propionamide,MS: 620 (M+H)⁺ :

N-[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-γ-oxo-α-(1-naphthylmethyl)-4-morpholinebutyramideMS: 702 (M+H)⁺.

EXAMPLE 38

90 mg (0.23 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 0.047 ml of Hunig base in 2ml of acetonitrile were treated dropwiseat room temperature with a solution of 60.7 mg of(S)-α-[(3,3-dimethylbutyryl)oxy]hydrocinnamic acid and 101 mg of BOP in5 ml of acetonitrile. The mixture was stirred at room temperature for 4hours, subsequently poured into 2N sodium bicarbonate solution andextracted with methylene chloride. The organic phase was washed withammonium chloride solution and dried over sodium sulfate. The solventwas removed under reduced pressure and the residue was chromatographedon silica gel. After elution with a 20:1 mixture of methylene chlorideand methanol, there were obtained 50 mg (34%) of(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl3,3-dimethylbutyrate as a yellow oil. MS: 637 (M+H)⁺.

The (S)-α-[(3,3-dimethylbutyryl)oxy]hydrocinnamic acid used as thestarting material was prepared as follows:

2.1 g (8.2 mmol) of (S)-2-hydroxy-3-phenylpropionic acid benzyl ester¹⁵and 1.24 ml of triethylamine in 100 ml of methylene chloride weretreated dropwise at room temperature within 2 hours with 1.26 ml oft-butylacetyl chloride. Thereafter, the reaction mixture was stirred at40° for 6 hours. Subsequently, the mixture was poured into water andextracted with methylene chloride. After drying over sodium sulfate, thesolvent was removed under reduced pressure and the crude product waspurified by flash chromatography on silica gel with a 1:3 mixture ofether and petroleum ether, to obtain 1.4 g (48%) of(S)-α-[(2,3-dimethylbutyryl)oxy]hydrocinnamic acid benzyl ester. MS: 238[M-(CH₃)₃ CCH₂ COOH]⁺.

The 1.4 q (3.95 mmol) of the benzyl ester thus obtained were dissolvedin 80 ml of ethanol and hydrogenated at room temperature for 2 hours andin the presence of 0.4 g of palladium-on-carbon. Filtration of thecatalyst and evaporation of the solvent under reduced pressure yielded 1g (96%) of (S)-α-[(3,3-dimethylbutyl)oxy]hydrocinnamic acid as acolorless oil which was used directly in the next step.

EXAMPLE 39

100 mg (0.394 mmol) of(αS,βS)-β-amino-α-[(S)-2--isopropyl-3-butenyl]cyclohexanepropanol in amixture of 3.5 ml of dimethylformamide and 7 ml of acetonitrile weretreated at room temperature with 0.079 ml of Hunig base. Thereafter, 174mg of BOP and 150 mg (0.394 mmol) of(S)-α-(dibenzylacetoxy)imidazole-4-propionic acid were added thereto andthe solution was stirred at room temperature for 6 hours. The mixture isthen diluted with 60 ml of ethyl acetate and washed with 1N hydrochloricacid and sodium bicarbonate solution. The organic phase was dried oversodium sulfate and the solvent was removed under reduced pressure. Theresidue was chromatographed on silica gel with a 10:1 mixture ofmethylene chloride and methanol, to obtain 179 mg of(S)-1-[[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-(imidazol-4-yl)ethyldibenzylacetateas an amorphous powder. MS: 596 (M--OH)⁺.

The (S)-α-(dibenzylacetoxy)imidazole-4-propionic acid used above as thestarting material was prepared as follows:

Dry hydrochloric acid gas was conducted at 0° for 3 minutes through asuspension of 2.5 g of α-hydroxy imidazolepropionic acid¹⁶ in 80 ml ofbenzyl alcohol, and the solution so obtained was allowed to stand atroom temperature for 12.20 hours. The excess benzyl alcohol wasdistilled off in a high vacuum and the residue was dissolved inmethylene chloride and washed with sodium bicarbonate solution. Theorganic phase was dried over sodium sulfate and evaporated under reducedpressure. The residue was purified by flash chromatography on silica gelwith a 10:1 mixture of methylene chloride and methanol, to obtain 3.5 g(89%) of (S)-α-hydroxyimidazolepropionic acid benzyl ester as a yellowoil. MS: 246 (M)⁺.

6.19 ml (48.3 mmol) of benzenesulfonyl chloride were

added dropwise at -5° to 10.53 g (43.8 mmol) of dibenzyl acetic acid in50 ml of pyridine, and the reaction solution was stirred at roomtemperature for 30 minutes. Subsequently, a solution of 6 g (24.4 mmol)of (S)-α-hydroxyimidazolepropionic acid benzyl ester in 5 ml of pyridinewas added dropwise at -5° and the solution was stirred at 0° for 2 hoursand thereafter at room temperature for 2 hours. The reaction mixture wasthen poured onto 3N hydrochloric acid/ice and extracted with ethylacetate. The organic extracts were thereafter washed with 2N sodiumbicarbonate solution, dried over sodium sulfate and evaporated underreduced pressure. The residue was flash chromatographed on silica gelusing a 15:1 mixture of methylene chloride and ethyl acetate, to obtain6.35 g (47%) of a 1:1 mixture of(S)-α-dibenzylacetoxy-N-(phenylsulfonyl)imidazole-4-propionic acidbenzyl ester and (S)-α,N-bis(dibenzyl-acetoxy)imidazole-4-propionic acidbenzyl ester as a yellow oil which was used in the next step withoutfurther purification.

95 ml of a 0.3N hydrochloric acid/methanol solution were added to 5.74 g(9.4 mmol) of the above mixture in 25 ml of methanol and stirred at roomtemperature for 2 hours. The mixture was poured into ice/sodiumbicarbonate and the product was extracted with ethyl acetate, dried oversodium sulfate and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography on silica gel, to obtain3.2 g (70%) of (S)-α-(dibenzylacetoxy)-imidazole-4-propionic acid benzylester. MS =468 (M)⁺.

3.2 g (6.83 mmol) of (S)-α-(dibenzylacetoxy)imidazole-4-propionic acidbenzyl ester in 150 ml of methanol were hydrogenated at room temperaturefor 2 hours in the presence of 660 mg of palladium-on-carbon. Thecatalyst was filtered off and the filter residue was washed severaltimes with a 1:1 mixture of methylene chloride and methanol. Thesolution was concentrated under reduced pressure until crystallizationoccurred. Recrystallization of the crystallizate from methylenechloride/methanol yielded 2.5 g (96%) of(S)-α-(dibenzylacetoxy)imidazole-4-propionic acid, melting point 210°.

EXAMPLE 40

442 mg (1 mmol) of BOP and 0.204 ml of Hunig base were added to 236.2 mg(1 mmol) of R-(+)-α-benzylsuccinic acid monoethyl ester¹⁷ and 390.6 mg(1 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidein acetonitrile and the solution obtained was stirred at roomtemperature for 20 hours. The reaction mixture was poured onto 1Nhydrochloric acid/ice and extracted with ethyl acetate. The organicextracts were washed with sodium bicarbonate solution, dried over sodiumsulfate and evaporated. The residue was chromatographed on silica gelwith a 10:1 mixture of methylene chloride and methanol as the elutingagent, to obtain 465 mg (76%) of ethyl(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrateas an amorphous powder. MS: 609 (M+H)⁺.

EXAMPLE 41

181 mg (0.404 mmol) of BOP and 0.083 ml of Hunig base were added to 66.5mg (0.404 mmol) of (S)-(+)-α-methylhydrocinnamic acid18 and 157 mg(0.404 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidein 10 ml of acetonitrile and stirred at room temperature for 16 hours.The reaction solution was poured into 1N hydrochloric acid/ice andextracted with ethyl acetate. The organic extracts were washed withsodium bicarbonate solution and dried over sodium sulfate. The solventwas then removed under reduced pressure and the residue waschromatographed on silica gel with a 10:1 mixture of methylene chlorideand methanol, to obtain 136 mg (63%) ofN-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[(S)-α-methylhydro-cinnamamido]imidazole-4-propionamideas an amorphous solid. MS: 537 (M+H)⁺.

EXAMPLE 42

135 mg of BOP and 0.062 ml of Hunig base were added to 73 mg ofα-methylcinnamic acid and 117.75 mg of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidein 5 ml of acetonitrile and stirred at room temperature for 20 hours.The reaction solution was poured onto 3N hydrochloric acid/ice andextracted with ethyl acetate. The organic phase was washed with 2Nsodium carbonate solution and dried over sodium sulfate. The solvent wasthen removed under reduced pressure and the residue was chromatographedon silica gel with a 10:1 mixture of methylene chloride and methanol, toobtain 100 mg ofN-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[α-methylcinnamoyl]-amino]-imidazole-4-propionamideas an amorphous solid. MS: 535 (M+H)⁺.

EXAMPLE 43

106 mg (0.404 mmol) of t-butoxycarbonyl-α,β-dehydrophenylalanine¹⁹ and157 mg of (S)-α-aminoN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidein 10 ml of acetonitrile were treated with 181 mg of BOP and 0.083 ml ofHunig base and subsequently stirred at room temperature for 16 hours.Thereafter, the solution obtained was poured onto 1N hydrochloricacid/ice, extracted with ethyl acetate, washed with 2N sodium carbonatesolution, dried over sodium sulfate, and the solvent was removed underreduced pressure. The residue was chromatographed on silica gel with a20:1 mixture of methylene chloride and methanol, to obtain 144 mg (54%)of (S)-α-[α-(t-butoxycarbonylamino)cinnamoyl]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideas an amorphous solid. MS: 636 (M+H)⁺.

EXAMPLE 44

100 mg (0.256 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 0.052 ml of Hunig base in 2 ml of acetonitrile were treated with 92mg of (S)-α-(diphenylacetoxy)hydrocinnamic acid and 113 mg of BOP in 2ml of acetonitrile and stirred at room temperature for 12 hours. Thereaction solution was then poured onto 1N hydrochloric acid/ice,extracted with ethyl acetate, the organic phase was washed with sodiumcarbonate solution, dried over sodium sulfate and, finally, the solventwas removed under reduced pressure. The residue was chromatographed onsilica gel with a 10:1 mixture of methylene chloride and methanol, toobtain 130 mg of(S)-α-[[(S)-1-[[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyldibenzylacetate in the form of an amorphous solid. MS 733 (M+H)⁺.

The (S)-α-(diphenylacetoxy)hydrocinnamic acid used as the startingmaterial was prepared as follows:

1.06 g (5 mmol) of diphenylacetic acid in 5 ml of pyridine were treateddropwise at -5° with 0.833 ml (6.5 mmol) of benzenesulfonyl chloride andthe solution was subsequently stirred at room temperature for 30minutes. Then, 1.28 g (5 mmol) of (S)-2 hydroxy 3-phenylpropionic acidbenzyl ester²⁰ in 5 ml of pyridine were added and the mixture wasstirred at 0°-10° for 2 hours and at room temperature for a further 2hours. The reaction solution was treated with water and extracted withethyl acetate. The organic phases were washed with 1N hydrochloric acidand sodium bicarbonate solution and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure and the residue was flashchromatographed on silica gel with a 4:1 mixture of petroleumether/ether, to obtain 1.8 g (80%) of benzyl(S)-α-(diphenylacetoxy)hydrocinnamate in the form of a yellow oil. MS:359 (M-benzyl)⁺.

The 1.8 g of the above-named benzyl ester were dissolved in 180 ml ofacetic acid, treated with 300 mg of palladium-on-carbon and hydrogenatedat room temperature until the theoretical amount of hydrogen had beentaken up (approximately 2 hours). The catalyst was then filtered off andthe solvent was removed under reduced pressure, upon which the desiredacid began to crystallize out slowly. Filtration of the separatedcrystals yielded 1.3 g (90%) of (S)-α-(diphenylacetoxy)hydrocinnamicacid. MS: no mol peak 212 (diphenylacetic acid)⁺ 167 (diphenylmethyl)⁺.

EXAMPLE 45

100 mg of(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol in 20ml of acetonitrile were treated with 0.080 ml of Hunig base, 174 mg ofBOP and 140 mg of (S)-3-carbamoyl-2-(dibenzylacetoxy)propionic acid andstirred at room temperature for 12 hours. Thereafter, the reactionsolution was poured onto 1N hydrochloric acid/ice, extracted with ethylacetate, the extracts were washed with sodium carbonate solution and,finally, dried over sodium sulfate. The solvent was then removed underreduced pressure and the residue was chromatographed on silica gel witha 20:1 mixture of methylene chloride and methanol, to obtain 142 mg(60%) of (S)-2-carbamoyl-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]- carbamoyl]ethyl dibenzylacetate in theform of a resin. MS: 591 (M+H)⁺.

The (S)-3 carbamoyl-2-(dibenzylacetoxy)propionic acid used as thestarting material was prepared as follows:

480 mg (2 mmol) of dibenzylacetic acid in 3 ml of pyridine were treatedat -5° with 0.34 ml of benzenesulfonyl chloride and subsequently stirredat room temperature for 30 minutes. Thereafter, 447 mg (2 mmol) ofbenzyl (S)-β-malamidate were added and the reaction solution was stirredat 0° for 2 hours and then at room temperature for 2 hours. The reactionsolution was then diluted with 100 ml of ethyl acetate, dilutehydrochloric acid was added, and the two phases obtained were separated.The organic phase was washed with sodium carbonate solution, dried oversodium sulfate and evaporated under reduced pressure. Chromatography ofthe residue on silica gel using a 4:1 mixture of methylene chloride andethyl acetate as the elutinq agent yielded 539 mg (59%) of benzyl(S)-3-carbamoyl 2-(dibenzyl acetoxy)propionate in the form of a yellowoil. MS: 354 (M-benzyl)⁺.

520 mg of the above-named benzyl ester in 5 ml of methanol werehydrogenated at room temperature for two hours in the presence of 100 mgof palladium-on-carbon. Thereafter, the catalyst was filtered off andthe solvent was removed under reduced pressure to obtain 370 mg (90%) of(S)-3-carbamoyl-2-(dibenzyl-acetoxy)propionic acid as a white solid. MS:338 (M--NH₃)⁺.

EXAMPLE 46

100 mg (0.256 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideand 0.052 ml of Hunig base in 2 ml of acetonitrile were treated at roomtemperature with 100 mg of N-(dibenzylcarbamoyl)-3-phenyl-L-alanine and113 mg of BOP and subsequently stirred at room temperature for 12 hours.Thereafter, the reaction solution was poured onto 1N hydrochloricacid/ice, extracted with ethyl acetate, the extracts were dried oversodium sulfate and the solvent was removed under reduced pressure.Chromatography of the residue on silica gel using a 10:1 mixture ofmethylene chloride and methanol as the eluting agent yielded 130 mg of1,1-dibenzyl-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]ureain the form of an amorphous solid. MS: 761 (M+H)⁺.

The N-(dibenzylcarbamoyl)-3-phenyl-L-alanine used as the startingmaterial was prepared as follows:

1 g (5.06 mmol) of dibenzylamine and 1.73 ml (10.1 mmol) of Hunig basein 50 ml of methylene chloride were treated dropwise while cooling withice with 2.6 ml of phosgene in toluene (20%. 5.06 mmol) and the solutionobtained was stirred at 0° for 3 hours. Then, 1.1 g of L-phenylalaninemethyl ester were added and the mixture was heated to 40° for 12 hours.Thereafter, the reaction mixture was poured into water, extracted withmethylene chloride and the extracts were dried over sodium sulfate. Thesolvent was then removed under reduced pressure and the residue waschromatographed on silica gel using a 15:1 mixture of methylene chlorideand ether as the eluting agent, to obtain 900 mg (45%) ofN-(dibenzylcarbamoyl)-3-phenyl-L-alanine methyl ester as a white solid.MS: 402 (M)⁺.

900 mg (2.23 mmol) of the above-named methyl ester in 20 ml of ethanolwere treated with 9 ml of 0.5N sodium hydroxide solution (4.46 mmol) andheated to 40° for 1 hour. Thereafter, the reaction solution wasacidified and the product was extracted with methylene chloride. Theorganic phase was dried over sodium sulfate and the solvent was removedunder reduced pressure, to obtain 100 mg (92%) ofN-(dibenzylcarbamoyl)-3-phenyl-L-alanine as an amorphous solid. MS: 388(M)⁺.

EXAMPLE 47

100 mg (0.52 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 0.052 ml of Hunig base in 2 ml of acetonitrile were treated at roomtemperature with 99 mg of N-(morpholinocarbamoyl)-3-phenyl-L-alanine and113 mg of BOP in 2 ml of acetonitrile and stirred at room temperaturefor 12 hours. Thereafter, the reaction solution was poured onto 1Nhydrochloric acid/ice, extracted with ethyl acetate, the organicextracts were dried over sodium sulfate and the solvent was removedunder reduced pressure. The residue was chromatoqraphed on silica gelwith a 10:1 mixture of methylene chloride and methanol, to obtain 130 mg(67%) of (S)-N-[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5hexenyl]-α-2-[N-(morpholinocarbamoyl)-3-phenyl-L-alanyl]amino]imidazole-4-propionamideas an amorphous solid. MS: 651 (M+H)⁺.

The N-(morpholinocarbamoyl)-3-phenyl-L-alanine used as the startingmaterial was prepared as follows:

3.6 ml of phosgene in toluene (20%. 6.95 mmol) were added dropwise whilecooling with ice to 0.6 ml (6.95 mmol) of morpholine and 2.4 ml (13.9mmol) of Hunig base in 20 ml of methylene chloride, and the solution wasstirred at 0° for 3 hours. Thereafter, 1.5 g (6.95 mmol) ofphenylalanine methyl ester hydrochloride were added and the reactionsolution was stirred at 40° for 12 hours. Subsequently, the reactionsolution was poured onto ice and extracted with methylene chloride. Theorganic phase was dried over sodium sulfate and evaporated under reducedpressure. Chromatography of the residue on silica gel using a 2:1mixture of methylene chloride and ether as the eluting agent yielded 400mg (20%) of N-(morpholino-carbamoyl)-3-phenyl-L-alanine methyl ester inthe form of a resin. MS: 292 (M)⁺.

400 mg (1.37 mmol) of the above-mentioned methyl ester in 10 ml ofethanol were treated with 5.5 ml of 0.5N sodium hydroxide solution (2.75mmol). The reaction mixture was then stirred at 40° for 1 hour,subsequently poured onto 3N hydrochloric acid/ice, extracted withmethylene chloride, the organic extracts were dried over sodium sulfateand, finally, the solvent was removed under reduced pressure. There werethus obtained 210 mg (55%) of N-(morpholinocarbamoyl)-3-phenyl-L-alaninein the form of an amorphous solid. MS: 278 (M)⁺.

EXAMPLE 48

A solution of 100 mg (0.256 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,0.052 ml of Hunig base. 113 mg of BOP and 81 mg ofN-(t-butoxycarbonyl)-β-pyrazol-1-yl-L-alanine²¹ in acetonitrile wasstirred at room temperature for 12 hours. Thereafter, the reactionmixture was poured onto 1N hydrochloric acid/ice, extracted with ethylacetate, the extracts were dried over sodium sulfate and the solvent wasfinally removed under reduced pressure. Chromatography of the residue onsilica gel with a 7:1 mixture of methylene chloride and methanol yielded80 mg (50%) of white crystals of t-butyl[(S)-1-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl-2-pyrazol-1-ylethyl]carbamate.MS: 628 (M+H)⁺.

EXAMPLE 49

A solution of 103 mg of N-[[2-(4-biphenyloxy)ethyl]carbamoyl]-3-phenyl-L-alanine and 113 mg of BOP in acetonitrile wasadded to 100 mg (0.256 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide0.052 ml of Hunig base in 5 ml of acetonitrile, and the mixture wassubsequently stirred at room temperature for 12 hours. Subsequently thereaction mixture was poured onto 1N hydrochloric acid/ice, extractedwith ethyl acetate, the extracts were dried over sodium sulfate andevaporated to dryness under reduced pressure. The crude product waspurified by chromatography on silica gel with a 10:1 mixture ofmethylene chloride and methanol, to obtain 90 mg (45%) of1-[2-(4-biphenyloxy)ethyl]-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]urea as an amorphous powder. MS: 777 (M+H)⁺.

The N-[[2-(4-biphenyloxy)ethyl]carbamoyl]-3-phenyl-L-alanine used as thestarting material was prepared as follows:

4.8 ml of Hunig base and 7 ml of a 20% phosgene solution in toluene wereadded at 0° to 3 g (14.06 mmol) of 2-(4-biphenyloxy)ethylamine²² in 100ml of toluene and the reaction mixture was subsequently stirred at 0°for one hour. Thereafter, 6 g of L-phenylalanine benzyl ester were addedand the solution was stirred at 90° for 12 hours. Thereafter, thereaction mixture was worked-up in the usual manner and the crude productwas purified by chromatography on silica gel with a 10:1 mixture ofmethylene chloride and methanol, to obtain 4.5 g (67%) ofN-[[2-(4-biphenyloxy)ethyl]carbamoyl]-3-phenyl-L-alanine benzyl ester.

4.5 g (9.4 mmol) of the above-named benzyl ester in 250 ml of ethanolwere hydrogenated at room temperature in the presence of 0.5 g ofpalladium-on-carbon until the theoretical amount of hydrogen had beentaken up. The catalyst was filtered off, the solvent was evaporatedunder reduced pressure, and the residue was recrystallized fromether/methylene chloride/methanol, to obtain 2.1 g (55%) ofN-[[2-(4-biphenyloxy)ethyl]carbamoyl]-3phenyl-L-alanine, melting point175° ; [α]₅₈₉.sup.° =+8.4° (c=1%, methanol).

EXAMPLE 50

A solution of 100 mg of (S)-α-[(dibenzylcarbamoyl)oxy]hydrocinnamic acidand 113 mg of BOP in 2 ml of acetonitrile was added to 100 mg (0.256 mg)of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and 0.052 ml ofHenig base in 5 ml of acetonitrile, and the mixture was subsequentlystirred at room temperature for 12 hours. The working-up was effected inthe usual manner. There were thus obtained 150 mg (77%) of(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyldibenzyl carbamate. MS: 762 (M+H)⁺.

The (S)-α-(dibenzylcarbamoyloxy)hydrocinnamic acid used as the startingmaterial was prepared as follows:

2.23 ml (4.3 mmol) of a 20% phosgene solution in toluene were addeddropwise while cooling with ice to 1.0 g (3.9 mmol) of(S)-2-hydroxy-3-phenylpropionic acid and 1.68 ml (3.9 mmol) of Hunigbase in 20 ml of tetrahydrofuran, and the mixture was subsequentlystirred at 0°-10° for 1.5 hours. Then, 0.824 ml (4.3 mmol) ofdibenzylamine in 20 ml of tetrahydrofuran were added dropwise and thereaction solution was stirred at room temperature for a further 12hours. Subsequently, the mixture was poured on to ice, neutralized withpotassium bicarbonate solution and extracted with ethyl acetate. Forpurification, the crude product obtained was flash chromatographed onsilica gel using a 3:1 mixture of petroleum ether and ether, to obtain825 mg (42%) of (S)-α-[(benzyloxy)carbonyl]phenethyl dibenzyl carbamateas a resin. MS: 388 (M-benzyl)⁺.

0 8 g of the above-described benzyl ester was hydrogenated at roomtemperature for 2.5 hours in 30 ml of a 4:1 mixture of methanol andethyl acetate, in the presence of 80 mg of palladium-on-carbon.Thereafter, the catalyst was filtered off and the solvent was evaporatedunder reduced pressure. There were thus obtained 461 mg (73%) of(S)-α-[(dibenzylcarbamoyl)oxy]hydrocinnamic acid in the form of a resin.MS: 389 (M)⁺.

EXAMPLE 51

A solution of 100 mg of ethyl(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyratein 30 ml of methanol was saturated with ammonia for 1-2 minutes andsubsequently left to stand at room temperature for 12 hours. Thereafter,the solvent was removed under reduced pressure and the residue waschromatographed on silica gel with 10% methanol in methylene chloride asthe eluting agent, to obtain 63 mg (66%) of(S)-α-[(R)-α-(carbamoylmethyl)hydrocinnam-amido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideas a resin. MS: 580 (M+H)⁺.

EXAMPLE 52

A solution of 84.62 mg (0.3 mmol) oft-butoxycarbonyl-α-methyl-D,L-phenylalanine, 135 mg of BOP, 118 mg of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 0.062 ml of Hunig base was stirred at room temperature for 12 hours.The reaction mixture was worked-up as described in Example 48, to obtain125 mg (64%) of t-butyl [(R orS)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-α-methylphenethyl]carbamateas an epimer mixture. The two epimers can be separated by chromatoqraphyon silica gel with 10% methanol in methylene chloride. The more polarepimer has a Rf value of 0.38, while the less polar has a Rf value of0.46. MS: 652 (M+H)⁺.

The t-butoxycarbonyl-α-methyl-D,L-phenylalanine used as the startingmaterial was prepared as follows:

2.44 g (11.16 mmol) of di-t-butyl dicarbonate in 5 ml of t-butyl alcoholwere added dropwise at room temperature to 2.0 g (11.16 mmol) ofα-methyl-D,L-phenylalanine in 11.16 ml of 1N sodium hydroxide solutionand 10 ml of t-butyl alcohol, and the reaction mixture was subsequentlystirred at room temperature overnight. Thereafter, water was added, themixture was washed with pentane, the aqueous phase was adjusted to pH 2by the addition of potassium bisulfate solution and extracted with ethylacetate. The organic phase was then dried over sodium sulfate andconcentrated, to give 1.56 g (50%) oft-butoxycarbonyl-α-methyl-D,L-phenylalanine as a white powder which wasused directly in the next step.

EXAMPLE 53

A mixture of 100 mg (0.45 mmol) of N-benzyl-3-carbamoyl-D-alanine, 187mg (0.45 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy4-isopropyl-5-hexenyl]imidazole-4-propionamide 0.093 ml of Hunig baseand 202 mg of BOP in 10 ml of a 2:1 mixture of acetonitrile anddimethylformamide was stirred at room temperature for 18 hours.Thereafter, the reaction mixture was poured into aqueous ammoniumchloride solution, extracted with ethyl acetate, the extracts werewashed with sodium carbonate solution, dried over sodium sulfate andevaporated to dryness under reduced pressure. Chromatography of theresidue on silica gel with 10% methanol in methylene chloride as theeluting agent yielded 87 mg (32%) of (S)-α-[(R)-2-(benzylamino)3-carbamoylpropionamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideas a resin. MS: 595 (M+H)⁺.

The N-benzyl-3-carbamoyl-D-alanine used as the starting material wasprepared as follows:

1.5 g (10 mmol) of D-asparagine hydrate in 5 ml of 2N sodium hydroxidesolution were treated with 1.01 ml (10 mmol) of benzaldehyde and thereaction mixture was stirred homogeneously at room temperature for 20minutes. Subsequently, 114 mg (3 mmol) of sodium borohydride were addedportionwise, the mixture was stirred at room temperature for 30 minutes,a further 114 mg of sodium borohydride were added and, finally, themixture was stirred at room temperature for a further 30 minutes.Thereafter, the aqueous phase was washed with methylene chloride andthen adjusted to pH 6-7 with 1N hydrochloric acid, upon whichcrystallization occurred. The separated crystals were filtered off,washed with water and ether and finally dried in a high vacuum, toobtain 0.6 g (27%) of N-benzyl-3-carbamoyl-D-alanine as a white powder.MS 223 (M+H)⁺.

EXAMPLE 54

80 mg (0.13 mmol) of ethyl(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyratewere taken up in 2 ml of a 5.6 molar alcoholic dimethylamine solutionand heated to reflux for 3 hours. The solution was then evaporated andthe residue was chromatographed on silica gel with a 20:1 mixture ofmethylene chloride and methanol to obtain 33 mg (20%) of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(R)-α-[(dimethylcarbamoyl)methyl]hydrocinnamamido]imidazole-4-propionamide as an amorphous powder.MS: 608 (M+H)⁺.

EXAMPLE 55

The following compounds were prepared in a manner analogous to thatdescribed in Example 40:

From 117 mg (0.3 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 75 mg (0.3 mmol) of N-benzyl-3-ethoxycarbonyl-D-alanine, 85 mg (45%)of ethyl(R)-3-(benzylamino)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]propionateas an amorphous powder. MS: 624 (M+H)⁺ ;

From 117 mg (0.3 mmol) of(S)-α-amino-α-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy4-isopropyl-5-hexenyl]-imidazole-4-propionamide and 88 mg (0.3 mmol) ofN-benzyloxycarbonyl-L-asparagine. 136 mg (71%) of benzyl[(S)-1-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-2-carbamoylethyl]carbamateas an amorphous powder MS: 639 (M+H)⁺ ;

From 157 mg (0.4 mmol) of(S)-a-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 136 mg (0.4 mmol) of N-benzoyl-γ-benzyl-D-glutamate, 115 mg (40%) ofbenzyl (S)-4-benzamido-4-[[(3)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl].-2-imidazol-4-ylethyl]carbamoyl]butyrate. MS: 714 (M+H)⁺ ;

From 100 mg of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 64 mg of (RS)-α-[[(2-hydroxyethyl)carbamoyl]methyl] -hydrocinnamicacid, 50 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(RS)-α-[[(2-(hydroxethyl)carbamoyl]methyl]hydrocinnamido]imidazole-4-propionamideas a 1:1 epimer mixture MS: 624 (M+H)⁺ ;

From 100 mg of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-α-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 80 mg of α-[(phenethylcarbamoyl)methyl]cinnamic acid, 65 mg (37%) of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[α--[(phenethylcarbamoyl)methyl]cinnamamido]imidazole-4-propionamide,MS: 682 (M+H)⁺ ;

From 214 mg (0.55 mmol) of(S)-α-amino-N-[(1S,2S,4S)-]-(cyclohexylmeIhyl)-2-hydroxy-4-isopropyl-5-exenyl]imidazole-4-propionamideand 160 mg (0.55 mmol) of (RS)-α-[2-(morpholinocarbonyl)ethyl]hydrocinnamic acid, 210 mg (60%) of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(RS)-α-[2-(morpholino-carbonyl)ethyl]hydrocinnamyl]imidazole-4-propionamideas a 1:1 epimer mixture, MS: 664 (M+H)⁺ ;

From 100 mg (0.25 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 100 mg (0.28 mmol) ofN-[(4-biphenylmethyl)carbamoyl]-3-phenyl-L-alanine, 150 mg (77%) of1-(4-biphenylmethyl) 3-[(S)-1[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-L-carbamoyl]phenethyl]urea,MS: 748 (M+H)⁺.

The respective acids used as the starting materials were prepared asfollows:

N-Benzyl-3-ethoxycarbonyl-D-alanine

574 mg (2.9 mmol) of β-ethyl-D-aspartic acid, which was preparedaccording to the method described by Pivitti in Gazetta, 18, 480 (1888)for the preparation of the racemic compound, were dissolved in 2.9 ml of2N sodium hydroxide solution and treated with 0.3 ml of benzaldehyde andsubsequently stirred vigorously at room temperature for one hour. 33 mgof sodium borohydride were then added and the mixture was stirred atroom temperature for a further hour. Thereafter, a further 33 mg ofsodium borohydride were added and the mixture was stirred at roomtemperature for a further hour. The mixture was subsequently extractedwith ether and the aqueous phase was adjusted to pH 6-7, upon whichcrystallization occurred. The separated crystals were filtered off anddried in a high vacuum, to obtain 81 mg (10%) ofN-benzyl-3-ethoxycarbonyl-D-alanine which was used directly in the nextstep. MS: 206 (M-COOH)⁺.

N-Benzoyl-γ-benzyl-D-qlutamate

γ-Benzyl-D-qlutamate was benzoylated according to the method describedby Miller and Waelsch in Arch. Biochem. Biophys. 1952, 35, 176 for thebenzoylation of γ ethyl-L-glutamate, to obtain the desired product in75% yieId, MS: 341 (M)⁺.

(RS)-α-[[(2-(Hydroxyethyl)carbamoyl]methyl]hydrocinnamic acid

150 mg (0.8mmol) of benzalsuccinic acid anhydride [S. G. Cohn et al.,JACS, 90, 3495 (1968)]in 10 ml of methylene chloride were treated with0.048 ml of ethanolamine and stirred at room temperature for 2 hours.The separated crystals were filtered off and dried, to obtain 155 mg(78%) of α-[[(2-(hydroxethyl)carbamoyl]methyl]cinnamic acid as colorlesscrystals. MS: 249 (M)⁺.

180 mg of the above-named acid in 5 ml of ethanol were hydrogenated atroom temperature for 2 hours in the presence of 2 ml ofpalladium-on-carbon. Thereafter, the catalyst was filtered off and thesolvent was removed under reduced pressure. The residue was dissolved inethyl acetate and washed with 0.1N hydrochloric acid. The organic phasewas dried over sodium sulfate and the solvent was evaporated underreduced pressure, to obtain 125 mg (70%) of(RS)-α-[[(2-hydroxyethyl)carbamoyl]methyl]hydrocinnamic acid which wasused directly in the next step. α-[(phenethylcarbamoyl)methyl]cinnamicacid

226 mg (1.2 mmol) of benzalsuccinic acid anhydride were treated in 20 mlof methylene chloride with 0.15 ml of 2-phenethylamine and subsequentlystirred at room temperature for 2 hours. The solvent was removed underreduced pressure and the residue was chromatographed on silica gel, toobtain 260 mg (70%) of α-[(phenethylcarbamoyl)methyl]cinnamic acid, MS:309 (M)⁺.

(RS)-α-[2-(Morpholinocarbonyl)ethyl]hydrocinnamic acid

2.5 g (10 mmol) of benzylmalonic acid diethyl ester and 1.45 ml (10mmol) of t-butyl acrylate in 5 ml of acetonitrile were treated with 1.49ml of DBU and stirred at room temperature for 6 hours. Thereafter, themixture was poured into dilute hydrochloric acid (pH 2), extracted withether, the organic phase was washed with a small amount of water, driedover sodium sulfate and the solvent was removed under reduced pressure.There were obtained 3.7 g (97%) of 4-t-butyl 2,2-diethyl1-phenyl-2,2,4-butanetricarboxylate as a pale yellow oil which was useddirectly in the next step.

1 9 g (5.4 mmol) of 4-t-butyl 2 2-diethyl1-phenyl-2,2,4-butanetricarboxylate in 20 ml of ethanol were treatedwith 27 ml of 2N sodium hydroxide solution (54 mmol) and subsequentlystirred at 50° for 6 hours. Thereafter, the reaction mixture wasextracted with ether, the extracts were dried over sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waschromatographed using a 10:1 mixture of methylene chloride and methanolas the eluting agent, to obtain 0.8 g (50%) of 3-ethyl 2,4-dihydrogen1-phenyl-[2,2,4]-butanetricarboxylate as an oil, MS: 250 (M-CO₂)⁺.

800 mg of 3-ethyl 2,4-dihydrogen 1-phenyl-2,2,4-butanetricarboxylatewere heated to 170° for 2 hours in a high vacuum and subsequentlychromatographed on silica gel by means of a 10:1 mixture of methylenechloride and methanol, to obtain 600 mg (88%) of(RS)-4-(ethoxycarbonyl)-5-phenylvaleric acid as an oil which was useddirectly in the next step. MS: 250 (M⁺),

600 mg (2.4 mmol) of (RS)-4-(ethoxycarbonyl)-5-phenylvaleric acid in 20ml of acetonitrile were treated with 1.06 g (2.4 mmol) of BOP, 310 mg ofHunig base and 0.21 ml of morpholine and stirred at room temperature for1 hour and thereafter at 50° for 2 hours. After the usual working-up andchromatography on silica gel using a 10:1 mixture of methanol andchloroform as the eluting agent, there were obtained 400 mg (52%) of(RS)-α-[2-(morpholinocarbonyl)ethyl]hydrocinnamic acid ethyl ester whichwas used directly in the next step. MS: 319 (M⁺).

400 mg (1.25 mmol) of the above-named ester in 10 ml of ethanol weretreated with 5 ml of 0.5N sodium hydroxide solution and subsequentlystirred at 50° for 2 hours. After the usual working-up andchromatography on silica gel using a 10:1 mixture of methylene chlorideand methanol there were obtained 170 mg (47%) of(RS)-α-[2-(morpholinocarbonyl)ethyl]hydrocinnamic acid as an oil whichwas used directly in the next step, MS: 291 (M⁺).

N-[(4-Biphenylmethyl)carbamoyl]-3-phenyl-L-alanine

3.9 g (21.3 mmol) of biphenylmethylamine²³ and 7.2 ml of Hunig base in200 ml of toluene were treated while cooling in a ice bath with 10.5 mlof phosgene in toluene (20%) and stirred at 0° for 1 hour. Thereafter, 9g of L-phenylalanine benzyl ester 4-toluenesulfonate were added and thesolution was stirred at 80° for 12 hours. Subsequently, the mixture waspartitioned between methylene chloride and water, the organic phase wasdried over sodium sulfate, the solvent was removed under reducedpressure, and the product was isolated by chromatography on silica gelusing a 10:1 mixture of methylene chloride and methanol, to obtain 7.3 g(74%) of N-[(4-biphenylmethyl)carbamoyl]-3-phenyl-L-alanine benzyIester.

3.2 g (6.7 mmol) of the above-named benzyl ester in 100 ml of ethanolwere hydrogenated at room temperature in the presence of 320 mg ofpalladium-on-carbon until the theoretical amount of hydrogen had beentaken up. Thereafter, the catalyst was filtered off, the filtrate wasevaporated and the residue was crystallized from ethanol/methylenechloride/ether, to obtain 2.1 g (65%) ofN-[(4-biphenylmethyl)carbamoyl]-3-L-alanine in the form of whitecrystals, melting point 169°-170°.

EXAMPLE 56

57 mg ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamide,21 mg of t-butoxycarbonyl-L-azetidine-2-carboxylic acid, which wasprepared from azetidinecarboxylic acid by t-butoxycarbonylationaccording to the method described by O. Keller et al. in Org. Synth. 63,160, 1985, 47 mg of BOP and 0.021 ml of Hunig base in 5 ml ofacetonitrile were stirred at room temperature for 8 hours and thereafterworked-up in the usual manner. The crude product was purified bychromatography on silica gel with a 10:1 mixture of methanol andchloroform, to obtain 69 mg of t-butyl[(S)-2-[(S)-α-[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]-1-azetidinecarboxylatein the form of white crystals. MS 721 (M+H)⁺.

EXAMPLE 57

56 mg of t-butyl[(s)-2-[(S)-α-[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]-carbamoyl]-1-azetidinecarboxylatein 5 ml of ethanol were hydrogenated at room temperature for 2 hours inthe presence of 10 mg of palladium-on-carbon. Thereafter, the catalystwas filtered off and the solvent was evaporated under reduced pressure,to obtain 47 mg of t-butyl(S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-azetidinecarboxylatein the form of white crystals. MS: 723 (M+H)⁺.

In an analogous manner by hydrogenating 90 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(RS)-α-[(cyclopentylcarbonyl)-methyl]hydrocinnamamido]imidazole-4-propionamidethere were obtained 78 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-α-[(RS)-α-[(cyclopentylcarbonyl)methyl]hydrocinnamamido]imdiazole-4-propionamidein the form of an amorphous solid as a 1:1 epimer mixture, MS: 635(M+H)⁺.

EXAMPLE 58

The following compounds were prepared in a manner analogous to thatdescribed in Example 56:

From 75 mg ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 30 mg of(3R,8aR)-hexahydro-8a-methyl-5-oxo-5H-thiazolo-[3.2-a]pyridine-3-carboxylicacid²⁴, 64 mg (64%) of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopro-pyl-5-hexenyl]-.alpha.-[(RS)-α-[(3R,8aR)-hexahydro-8a-methyl-5-oxo-5H-thiazolo-[3,2-a]pyridine-3-carboxamido]hydrocinnamamido]-imidazole-4-propionamideas a white solid, MS: 735 (M+H)^(+;)

From 75 mg ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenylL-alanyl)imidazole-4-propionamide and 30 mg of(3R,7aR)-tetrahydro-7a-methylpyrrolo[2.1-b]-thiazole-3-carboxylic acid²⁴86 mg of(3R,7aR)-N-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]hexahydro-5-oxo-pyrrolo[2,1-b]thiazole-3-carboxamideas an amorphous solid, MS: 721 (M+H)⁺ ;

From 75 mg ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 30 mg of N-t-butoxycarbonyl-L-methionine, 90 mg of t-butyl[(S)-1-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-phenethyl]carbamoyl]-2-(methylthio)ethyl]carbamate as an amorphous solid, MS: 769 (M+H)⁺ ;

From 75 mg ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 32 mg of N-isovaleryl-L-methionine which in turn was prepared byreactinq L-methionine methyl ester with isovaleric acid chloride andsubsequently saponifying of the methyl ester, 61 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[(S)-4-(methylthio)-2-isovaleramidobutyramido]hydrocinnamamido]-imidazole-4-propionamideas an amorphous solid,

MS:753 (M+H)⁺.

EXAMPLE 59

A mixture of 95 mg of(RS)-α-[(2-morpholinoethyl)carbamoylmethyl]-1-naphthalenepropionic acid,100 mg of (S)-α-amino-N-[(1S,2S.4S)-1-(cyclohexylmethyl)2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and 97 mg ofHBTU in acetonitrile was stirred at room temperature for 3.5 hours andthen worked-up in the usual manner. The residue was chromatographed onsilica gel with a 4: mixture of methylene chloride and methanol as theeluting agent, to obtain 60 mg ofN-[(1S,2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[3-[(2-morpholinoethyl)carbamoyl]-2-(1-naphthylmethyl)propionamido]imidazole-4-propionamideas a foam. MS: 743 (M+H)⁺.

The (RS)-α-[(2-morpholinoethyl)carbamoylmethyl]-1-naphthalenepropionicacid used as the starting material was prepared as follows:

0.72 g of DCC was added to 1.0 g (3.5 mmol) of(RS)-3-(ethoxycarbonyl)-4-(1-naphthyl)butyric acid²⁵ in 50 ml ofmethylene chloride and the suspension obtained was stirred at roomtemperature for 2 hours. Subsequently, 0.46 ml (3.5 mmol) of4-(2-aminoethyl)morpholine was added and the mixture was stirred at roomtemperature for a further 18 hours. After usual working-up, the residuewas flash chromatographed on silica gel with a 20:1 mixture of methylenechloride and methanol as the eluting agent, to obtain 0.5 g of(RS)-α-[(2-morpholinoethyl)carbamoylmethyl]-1-naphthalenepropionic acidethyl ester in the form of a Pale yellow resin. MS: 398 (M)⁺.

0.5 g (1.25 mmol) of the above-named ethyl ester in ethanol was treatedwith 2.5 ml of 1N sodium hydroxide solution and stirred at 80° for 6hours. Thereafter, the reaction mixture was adjusted to pH 6 and thesolvent was removed under reduced pressure. The residue was suspended ina 1:1 mixture of methylene chloride and methanol, the insoluble saltswere filtered off, the filtrate was dried over sodium sulfate and thesolvent was evaporated under reduced pressure. In this manner there wereobtained 500 mg of(RS)-α-[(2-morpholinoethyl)carbamoylmethyl]-1-naphthalenepropionic acidin the form of a yellow foam which was used directly in the next step.

EXAMPLE 60

A mixture of 153 mg (0.4 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]Imidazole-4-propionamide,98 mg of (R)-α-(pivaloylmethyl)hydrocinnamic acid, 175 mg of BOP and0.14 ml of Hunig base in 10 ml of acetonitrile was stirred at roomtemperature for 12 hours and thereafter worked-up in the usual manner.Chromatography of the residue on silica gel using a 10:1 mixture ofmethylene chloride and methanol as the eluting agent yielded 120 mg ofN-[(1S,2S,4S)-l-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-α-(α-pivaloylhydrocinnamamido)imidazole-4-propionamideas white crystals, MS: 615 (M+H)⁺.

The(S)-α-amino-N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideused as the starting material was prepared as follows:

In a manner analogous to that described in Example 1 for the preparationof(αS,βS)-β-t-butoxycarbonylamino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol,from 56.6 g (320 mmol) of (RS)-2-isopropyl-3-butenyl bromide 7.7 g ofmagnesium and 24.2 g of N-t-butoxycarbonyl-L-phenylalanal²⁶ there wereobtained 15.6 g (49%) of t-butyl[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamate as anepimer mixture. The desired (1S,2S,4S)-epimer was isolated as the lesspolar isomer. MS: 256 (M-benzyl)⁺, by flash chromatography on silica 5gel using a 9:1 mixture of methylene chloride and ether as the elutingagent.

of 1.22 g (2.83 mmol) of N-α-N-im-di-t-butoxycarbonyl-L-histidine. 700mg (2.83 mmol) of (2S,3S,5S)-2-amino-5-isopropyl-1-phenyl-6-hepten-3-ol,1.25 g of BOP and 0.58 ml of Hunig base in 20 ml of acetonitrile wasstirred at room temperature for 12 hours and thereafter worked-up in theusual manner. Chromatography of the residue on silica gel using a 2:1mixture of methylene chloride and ether yields 1.0 g (10%) of t-butyl4-[(S)-2-[[(1S,2S,4S)-1-benzy1-2-hydroxy-4-isopropy1-5-hexenyl]carbamoyl]-2-(1-t-butoxyformamido)ethyl]imidazole-1-carboxylatein the form of a foam, MS: 585 (M+H)⁺.

1 g (1.7 mmol) of t-butyl4-[(S)-2-[[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-(1-t-butoxyformamido)ethyl]imidazole-1-carboxylatewere dissolved in 7 ml of 5N hydrogen chloride in dioxane andsubsequently stirred at room temperature for 2 hours. Thereafter, thereaction mixture was poured into sodium carbonate solution and extractedwith ethyl acetate. The organic extract was dried and evaporated and theresidue was chromatographed on silica gel with a 3:1 mixture ofmethylene chloride and methanol, to obtain 340 mg (52%) of(S)-α-amino-N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propion-amideas a foam, MS; 385 (M+H)⁺.

EXAMPLE 61

120 mg ofN-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-α-(α-pivaloylhydrocinnamamido)imidazole-4-propionamidein 10 ml of ethanol were hydrogenated at room temperature for 2 hours inthe presence of 20 mg of palladium-on-carbon. Thereafter, the catalystwas filtered off and the solvent was evaporated under reduced pressure,to obtain(S)-N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropylhexyl]-α-[(R)-.alpha.-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide as a foam. MS: 617(M+H)⁺.

EXAMPLE 62

A mixture of 256 mg (1.03 mmol) of(2S,3S,5S)-2-amino-5-isopropyl-1-phenyl-6-hepten-3-ol, 414 mg ofBoc-Phe-His-OH. 0.354 ml of Hunig base and 455 mg of BOP in 20 ml ofacetonitrile was stirred at room temperature for 12 hours and thenworked-up in the usual manner. By flash chromatography of the residue onsilica gel using a 7:1 mixture of methylene chloride and methanol, therewere obtained 385 mg (61%) of t-butyl((S)-α-[[(RS)-1-[[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as a 4:1 epimer mixture. MS: 632 (M+H)⁺.

EXAMPLE 63

334 mg (0.53 mmol) of t-butyl[(S)-α-[[(RS)-1-[[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate were dissolved in 3 ml of 5.2N hydrogen chloride in dioxaneand the mixture was stirred at room temperature for 2 hours. After theusual working-up, 100 mg of the crude product obtained were dissolved in10 ml of acetonitrile. 40.4 ml (0.188 mmol) oft-butoxycarbonyl-D-proline, 0.064 ml of Hunig base and 83 mg of BOP wereadded, and the reaction mixture was subsequently stirred at roomtemperature for 12 hours. After the usual working-up the residue waschromatographed on silica gel using a 10:1 mixture of methylene chlorideand methanol to obtain 78 ml (56%) of t-butyl(R)-2-[[(S)-α-[(RS)-1-[[[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]1-pyrolidinecarboxylatein the form of white crystals as a 4:1 epimer mixture. MS: 729 (M+H)⁺.

EXAMPLE 64

0.65 g of(S)-α-amino-N-[(1S,2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamidein 20 ml of acetonitrile were added together with 0.36 ml ofethyldiisopropylamine to a solution of 0.45 g of2-benzyl-3-phenylpropionic acid (which was prepared according to themethod described in J. Am. Chem. Soc. 71 1863 (1949)) and 0.8 g of BOPin 30 ml of acetonitrile and the mixture was stirred at room temperaturefor 20 hours. Subsequently, the reaction mixture was evaporated underreduced pressure, the residue was dissolved in 50 ml of ethyl acetateand the organic solution was washed twice with 100 ml of water eachtime, dried over sodium sulfate and evaporated. The residue Wasseparated by flash chromatography on 100 g of silica gel with a 250:15mixture of methylene chloride and methanol as the eluting agent, toobtain there was obtained 0.17 g of(S)-α-(2,2-dibenzylacetamido)-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamide as awhite powder, melting point 120°. This compound corresponds to the lesspolar isomer and has a Rf value of 0.14.

The (S)-α-amino-N-[(1S, 2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamideused as the starting material was prepared as follows:

0.72 g of (4S)-amino-(5S)-hydroxy-7-isopropyl-2-methyl-8-nonene in 20 mlof dimethylformamide were added together with 0.7 ml ofethyldiisopropylamine to a solution of 2 g ofN-α-N-im-bis-Fmoc-L-histidine and 1.47 g of BOP in 20 ml ofdimethylformamide and the mixture was stirred at room temperature for 20hours. Subsequently, the reaction mixture was evaporated under reducedpressure, the residue was dissolved in 60 ml of ethyl acetate and theorganic phase was washed twice with 200 ml of water each time, driedover sodium sulfate and evaporated. The crude product was purified byflash chromatography on 100 g of silica gel with a 250;20 mixture ofmethylene chloride and methanol as the eluting agent, to obtain 1.25 gof fluoren-9-ylmethyl[(S)-1-[[(1S,2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl] carbamate as a white powder,MS: 573 (M+H)⁺.

1.25 q of fluoren-9-ylmethyl[(S)-1-[[(1S,2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamate were dissolved in 20 ml of piperidine and stirred at roomtemperature for 3 hours. Thereafter, the reaction mixture was pouredonto 20 ml of ice/water and filtered. Evaporation of the filtrateyielded 0.65 g of(S)-α-amino-N-[(1S,2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole4-propionamide as a white powder, Ms: 269 (M-C₄ H₅ N₂)⁺.

EXAMPLE 65

0.3 g of (S)-2-[[N-(t-butoxycarbonyl) 3-phenyl L-alanyl]oxy]succinamidicacid were dissolved together with 0.35 g of BOP in 20 ml of acetonitrilewith the addition of 2 ml of dimethylformamide, treated with a solutionof 0.17 g of (4S)-amino-(5S)-hydroxy-7-isopropyl 2-methyl-8-nonene and0.15 ml of ethyldiisopropylamine in 20 ml of acetonitrile and stirred atroom temperature for 20 hours. Subsequently, the reaction mixture wasevaporated under reduced pressure and the residue was dissolved in 50 mlof methylene chloride. The organic solution was washed in successionwith 50 ml of 3N hydrochloric acid, 50 ml of saturated sodiumbicarbonate solution and 50 ml of saturated sodium chloride solution,dried over sodium sulfate and evaporated. The residue was purified byflash chromatography on 50 g of silica gel using a 10:1 mixture ofmethylene chloride and methanol as the eluting agent and subsequentlycrystallized from ether/methylene chloride. In this manner there wasobtained 0.3 g of t-butyl [(S)-α-[[(S)-2-carbamoyl-1-[[(1S,2S,4RS)2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-ethoxy]carbonyl]phenethyl]carbamate as a white powder, melting point 75°.

The (4S)-amino-(5S)-hydroxy-7-isopropyl 2-methyl 8-nonene used as thestarting material was prepared as follows:

0.8 g of t-butoxycarbonyl-L-phenylalanine was dissolved in 5 ml ofpyridine, treated at -5° with 0.3 ml of oxalyl chloride and stirred at0-5° for 10 minutes. After the addition of 0.7 g ofbenzyl-(S)-3-carbamoyl-2-hydroxypropionic acid (which was preparedaccording to the directions in Agr. Biol. Chem. 40, 1651 (1976) and Int.J. Peptide Protein Res. 20, 35 (1982)) in 1 ml of pyridine, the mixturewas stirred at 0°-5° for 2 hours and thereafter at room temperature for1 hour. The reaction mixture was then poured onto ice and extractedtwice with 50 ml of ethyl acetate each time. The combined organicextracts were washed with 50 ml of 3N hydrochloric acid and 50 ml ofsaturated sodium bicarbonate solution, dried over sodium sulfate andevaporated. The residue was purified by flash chromatography on 50 g ofsilica gel using a 10:1 mixture of methylene chloride and methanol asthe eluting agent to obtain there was obtained 0.9 g of(S)-2-[[N-(t-butoxycarbonyl)-3-phenyl-L-alanyl]oxy]succinamide benzylester as a yellow powder. MS: 397 (M--C₄ H₉ O)⁺.

0.9 g of the above benzyl ester was dissolved in 40 ml of ethanol andhydrogenated at normal pressure in the presence of 0.1 g ofpalladium-on-carbon (10%). After completion of the hydrogen uptake, thecatalyst was filtered off and the filtrate was evaporated.Crystallization of the residue from methylene chloride yielded 0.52 g of(S)-2-[[N-(t-butoxycarbonyl)-3-phenyl-L-alanyl]oxy]succinamidic acid asa white powder, MS: 381 (M+H)⁺.

EXAMPLE 66

A solution of 200 mg of (2S,3S,5S)-2-[Boc-His(3-Bom)-Pro-His-NH]-1cyclohexyl-5-isopropyl-6-hepten-3-ol was hydrogenated exhaustively atroom temperature in a 4:1 mixture of glacial acetic acid and water, inthe presence of 20 mg of palladium-on-carbon (10%). After completion ofthe hydrogen uptake (4 hours), the catalyst was filtered off and thefiltrate was evaporated to dryness. The crystals obtained afterchromatographic purification on silica gel were recrystallized fromethyl acetate/hexane, to obtain there was obtained(2S,3S,5S)-2-(Boc-His-Pro-His-NH)-1-cyclohexyl-5-isopropyl-3-heptanol in69% yield, melting point 135°-136°.

The preparation of the(2S,3S,5S)-2-[Boc-His(3-Bom)-Pro-His-NH]-1-cyclohexyl5-isopropyl-6-hepten-3-ol used as the starting material was described inExample 68.

EXAMPLE 67

A solution of 100 mg of(S)-α-[[N-(t-butoxycarbonyl)-β-phenyl-L-alanyl]oxy]imidazole-4-propionicacid, 78 mg of(αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol and 55mg of N-methylmorpholine in 3 ml of dimethylformamide was treated with102 mg of HBTU while stirring and passage therethrough with argon. Afterallowing to stand overnight, the reaction solution was poured into 5 mlof concentrated aqueous sodium bicarbonate solution and extracted withethyl acetate. The organic extracts were dried and evaporated underreduced pressure and the crude product obtained in purified bychromatography on silica gel with a 95:5 mixture of methylene chlorideand methanol as the eluting agent, to obtain t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclo- hexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazole-4-ylethoxy]carbonyl]phenethyl]carbamate was obtained in 22% yield, melting point 72°-75° (dec.).

The(S)-α-[[N-(t-butoxycarbonyl)-β-phenyl-L-alanyl]oxy]imidazole-4-propionicacid used as the starting material was prepared as follows:

1.99 g of N-t butoxycarbonyl-L-phenylalanine and 1.58 g of benzyl(S)-α-hydroxyimidazolepropionate were suspended in 25 ml of methylenechloride and stirred. After stirring at room temperature for 15 minutes,305 mg of 4-dimethylaminopyridine were added and the reaction mixturewas cooled to -15°. After the dropwise addition of 2 ml ofN-methylmorpholine and a solution of 6.6 g of propanephosphoric acidanhydride in 5 ml of methylene chloride, the reaction mixture wasstirred at -15° for an additional 2 hours and left to stand at -18° for6 days. After the addition of a few drops of water, the reaction mixturewas evaporated under reduced pressure and the oily residue wastriturated for 2 hours with 100 ml of ethyl acetate and 25 ml of water.The organic phase was then washed in succession with aqueous sodiumbicarbonate solution (5%) water and 1.5M citric acid. The colorless oilobtained after evaporation of the solvent under reduced pressure waschromatographed on silica gel using a 95:5 mixture of methylene chlorideand methanol as the eluting agent, to obtain(S)-α-[[N-(t-butoxycarbonyl) 3-phenyl-L-alanyl]oxy]imidazole-4-propionic acid benzyl ester as a yellow oil in 13%yield, MS: 494 (M+H)⁺.

A solution of 960 mg of the above-described benzyl ester in 20 ml ofabsolute ethanol was hydrogenated in the presence of 500 mg ofpalladium-on-carbon (10%) until the theoretical amount of hydrogen hadbeen taken up. Thereafter, the catalyst was filtered off and thefiltrate was evaporated under reduced pressure, to obtain an oilyresidue which crystallized after the addition of methanol/ethyl acetate.In this manner there was obtained(S)-α-[[N-(t-butoxycarbonyl)-β-phenyl-L-alanyl]oxy]imidazole-4-propionicacid in 18% yield, melting point 130°-131°.

EXAMPLE 68

The following compounds were prepared in an analogous manner to thatdescribed in Example 67:

From(S)-α-amino-N-[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand N-(t-butoxycarbonyl)-3-(1-naphthyl)-L-alanine in 50% yield, t-butyl[(S)-1-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-2-(1-naphthyl)ethyl]carbamate, melting point 141°-143° (from ethyl acetate/hexane);

From (S)-α-amino-N-[(1S,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]imidazole-4-propionamide andN-(t-butoxycarbonyl)-4-chlorophenylalanine in 41% yield, t-butyl[(S)-1-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-2-(4-chlorophenyl)ethyl] carbamate, melting point220°-221° (from ethanol/ethyl acetate);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand N-t-butoxycarbonyl L-phenylglycine in 39% yield, t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-yl-ethyl]carbamoyl]benzyl]carbamate, melting point 125°-126° (from ethyl acetate/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]imidazole-4-propionamide andN-t-butoxycarbonyl-L-cyclohexylglycine in 54%. yield t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]cyclohexylmethyl]carbamate, melting point 139°-140° (from ethyl acetate/hexane);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]imidazole-4-propionamide and t-butoxycarbonyl-D-phenylalaninein 48% yield, t-butyl [(R)-α-[[(S)1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate, melting point 195° (from ethyl acetate);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5hexenyl]imidazole-4-propionamide andt-butoxycarbonyl-L-cyclohexylalanine in 22% yield, t-butyl[(S)-2-cyclohexyl-1-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl](2-imidazol-4-ylethyl]carbamoyl]ethyl]carbamate, melting point 116° (from ethyl acetate/diisopropyl ether);

FromN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand N-[5-(1-t-butoxyformamido)valeryl]-β-alanine in 40% yield, t-butyl[4-[[-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol4-ylethyl]-carbamoyl]phenethyl]carbamoyl]ethyl]carbamoyl]-butyl]carbamate, melting point 114°-115° (from ethyl acetate);

From(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]imidazole-4-propionamide and Boc-His(3-Bom)-Pro-OH in 51%yield, (2S,3S,5S)-2-[Boc-His(3-Bom)Pro-His-NH]-1-cyclohexyl-5-isopropyl-6-hepten-3-ol, melting point121°-122° (from ethyl acetate/hexane).

The acids used as the starting materials were either known andcommercially available or were prepared as follows:

N-[5-(I-t-Butoxyformamido)valeryl]-β-alanine

To a suspension of 7.68 g of β-alanine ethyl ester hydrochloride in 50ml of methylene chloride there was added, with stirring, 5.56 g oftriethyl- amine. 10.86 g of N-t-butoxycarbonyl-5-aminovaleric acid,dissolved in 50 ml of methylene chloride, and portionwise 11.35 g ofDCC, in that order. After completion of the addition, the reactionmixture was stirred at room temperature overnight and filtered off fromseparated urea. The filtrate was washed in succession with 250 ml ofsodium bicarbonate solution (5%), water, 250 ml of 0.1M citric acid and,finally, with saturated sodium chloride solution. Thereafter, thesolvent was evaporated under reduced pressure and the oily residue waspurified by column chromatography on silica gel, to obtainN-[5-(1-t-butoxyformamido)valeryl]-β-alanine ethyl ester in 59% yield,melting point 28° (from hexane).

3.94 g of this ester were dissolved in 20 ml of methanol and, whilestirring at 0°, 1 mol equivalent and after 30 minutes a further 0.2 molequivalents of 1N sodium hydroxide solution were added. The mixture wasthen stirred at room temperature for one hour, 1.2 mol equivalents of 1Nhydrochloric acid (PH 4) were added portionwise, the solvent wasevaporated under reduced pressure and the aqueous phase was extractedseveral times with methylene chloride. Drying and evaporation of theextracts yielded an oily residue which crystallized upon the addition ofhexane. Recrystallization from hexane yieldedN-[5-(1-t-butoxyformamido)valeryl]-β-alanine in 87% yield, melting point70°.

EXAMPLE 69

5 ml of a 4 molar solution of hydrogen chloride in dioxane were added to1.06 g (3 mmol) of t-butyl[(1S,2S,4S)-4-(2-furyl)-2-hydroxy-1-isobutyl-5-methylhexyl] carbamate in8 ml of acetic acid. After 30 minutes the solvent was evaporated underreduced pressure, the residue was digested with toluene, and the solventwas again evaporated. The residue was dissolved in 10 ml of absolutedimethylformamide and 1.8 g (3 mmol) of N-α-N-im-bis-Fmoc-L-histidine in10 ml of tetrahydrofuran, 0.35 ml of N-methylmorpholine and 0.8 g (5.6mmol) of N-hydroxybenzotriazole were added to the solution. Theresulting solution was cooled to -10° and treated dropwise with 5 ml ofa 1 molar DCC solution in tetrahydrofuran. The reaction mixture wasstirred overnight and filtered. The solution was treated with 5 ml of a50% piperidine-dimethylformamide solution and, after 30 minutes,evaporated in a high vacuum. The residue was dissolved in ether and theorganic phase was washed in succession with water, a sodium carbonatesolution and again with water. The organic phase was dried over sodiumsulfate and evaporated under reduced pressure. The residue was thendissolved in 10 ml of dimethylformamide and 0.8 g (3 mmol) ofN-t-butoxycarbonyl-phenylalanine in 10 ml of tetrahydro- furan, 0.35 mlof N-methylmorpholine, 0.8 g (5.6 mmol) of N-hydroxybenzotriazole and 5ml of a 1 molar DCC solution in tetrahydrofuran were added. The reactionmixture was stirred overnight and filtered. The filtrate was evaporatedin a high vacuum and the residue was dissolved in ether. The organicsolution was washed with water, a sodium carbonate solution and oncemore with water, dried over sodium sulfate and evaporated under reducedpressure. For purification, the residue was chromatographed with a 19:3mixture of methylene chloride and ethyl acetate as the eluting agent, toobtain 0.65 g of(S,S,S)-1-(Boc-Phe-His-NH)-methylbutyl-γ-isopropyl-2-furane-propanol asa thick oil. MS: 638 (M+H)⁺.

The t-butyl [(1S,2S,4S)-4-(2-furyl)-2-hydroxy-1-isobutyl-5-methylhexyl]carbamate used as the starting material was prepared as follows:

340 g (2.5 mmol) of zinc chloride were added in one portion to asolution of 217 g (1.67 mol) of 2,5-dimethoxy-2,5-dihydrofuran, 1500 ml(10 mol) of malonic acid diethyl ester, 167 ml of Water and 330 ml ofglacial acetic acid. The temperature rose to 35°. The dark solution wasstirred at room temperature overnight, poured onto ice, extracted threetimes with diethyl ether, washed in succession with saturated sodiumbicarbonate and sodium chloride solutions, and finally dried. Afterevaporating the excess malonic acid diethyl ester (70°/13 Pa), theremaining oil was distilled over a Vigreux column, to obtain 109.2 g(29%) of 2-furylmalonic acid diethyl ester (purity 94%), boiling point100°-110°/39 Pa.

24 g (1 mol) of sodium hydride were suspended in 100 ml of absolutetetrahydrofuran. A solution of 218.4 g (0.97 mol) of 2-furylmalonic aciddiethyl ester in 200 ml of absolute tetrahydrofuran was added dropwise.The temperature rose to 30° (blue suspension). After stirring at 30° for30 minutes, 340 g (200 ml; 2 mol) of isopropyl iodide were addeddropwise within 30 minutes. The reaction mixture was heated to refluxovernight, thereafter evaporated under reduced pressure, and dissolvedin ether. After evaporation of the solvent, the remaining oily residuewas distilled in a high vacuum, to obtain 240.6 g (92.5%) of2-furyl-2-isopropylmalonic acid diethyl ester (purity 93.6%) in the formof a yellowish oil, boiling point 85°-88°/13 Pa.

240.6 g (0.9 mol) of 2-furyl-2-isopropylmalonic acid diethyl ester weredissolved in 500 ml of dimethyl sulfoxide, treated with 2000 ml of 2Nsodium hydroxide solution and heated to reflux for 2 hours. Aftercooling, o the reaction mixture was poured into dilute sulfuric acid andextracted exhaustively with ether. The organic extracts were thereafterdried and the solvent was evaporated under reduced pressure, to obtain148.7 g (98%) of (±) 2-(2-furyl)-3-methyl- butyric acid in the form of athick yellowish oil.

161.0 g (0.96 mol) of (±) 2-(2-furyl)-3-methylbutyric acid weredissolved in 1000 ml of ether and treated with 109 g (0.9 mol) ofS(-)-α-phenylethylamine in 100 ml of ether. The separated crystals werefiltered off and recrystallized three times from 600 ml of ethylacetate, to obtain 80 g of white crystals, melting point 135°-136°,[α]_(D) ²⁰ =-14.1° (c=2%. methanol).

The crystals were suspended in ethyl acetate and acidified with a 3Nhydrochloric acid solution while cooling with ice. The organic solutionwas washed with water, dried and evaporated under reduced pressure, toobtain 46.7 g of (+) 2-(2-furyl)-3-methylbutyric acid as a viscous oil(purity 98.6%), [α]_(D) ²⁰ =+29.9° (c=1%, ethyl acetate).

The mother liquors from the above crystallizations were pooled and thefree acid was isolated as described, dissolved in 1000 ml of ether andtreated with the corresponding amount of R-(+)-α-phenylethylamine. Afterthree-fold recrystallization from ethyl acetate, there were obtained80.3 g of white crystals of melting point 135°-136°, [α]_(D) ²⁰ =+15.0°(c=1%, methanol).

Conversion of this salt according to the procedure described aboveyielded 45.0 g of (-)2-(2-furyl)-3-methylbutyric acid as a viscous oilof 99.5% purity. [α]_(D) ²⁰ =-31.1° (c=1%, ethyl acetate).

10.5 g (0.277 mol) of lithium aluminium hydride were suspended in 100 mlof absolute ether and treated while stirring within 10 minutes with 100ml of absolute tetrahydrofuran. To this stirred suspension was addeddropwise within 6-8 hours, while heating to reflux, 46.7 g (0.277 mol)of (+) 2-(2-furyl)-3-methylbutyric acid in 100 ml of absolutetetrahydrofuran. The reaction mixture was cooled and treated slowly witha 3N hydrochloric acid solution. The organic phase was separated, washedwith water, dried and evaporated under reduced pressure. The remainingoil was distilled in a high vacuum, to obtain 32 g (75%) of(R)-(+)-2-(2-furyl)-3-methyl-1-butanol as a colorless liquid of 96%purity, boiling point 58°/39 Pa, [α]_(D) ²⁰ =+2.5° (c=1%, ethanol).

121.7 g (0.464 mol) of triphenylphosphine were added portionwise within8 hours to a solution of 17.8 g (0.1154 mol) of(R)-(+)-2-(2-furyl)-3-methyl-1-butanol in 150 ml of carbontetrachloride. After stirring the reaction mixture for 24 hours, 500 mlof pentane were added and the precipitate formed was filtered off. Afterevaporation of the solvent, the residue was dissolved in pentane andpurified by chromatography on silica gel, to obtain 5 g (92%) of2-[(S)-(-)-1-(chloromethyl)-2-methylpropylfuran which was used directlyin the next step.

A solution of 14.6 g (0.084 mol) of2-[(S)-(-)-1-(chloromethyl)-2-methylpropylfuran in 46 ml of ether wereslowly added, dropwise, to a suspension of 3.22 g of magnesium in 12 mlof ether. The reaction mixture was stirred vigorously at roomtemperature overnight and thereafter cooled to -70°. 8.3 g (0.038 mol)of t-butoxycarbonyl-L-leucinal in 40 ml of ether were added dropwise.After completion of the addition, the reaction mixture was allowed tostand at 0° for 1 hour. Thereafter, 100 ml of a saturated ammoniumchloride solution were added, the organic phase was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue obtained (16 g) was chromatographed on silica gel with a 1:4mixture of ether and hexane, to obtain 4.8 g of t-butyl[(1S,2S,4S)-4-(2-furyl)-2-hydroxy-1-isobutyl-5-methylhexyl] carbamatewhich was used directly in the next step.

EXAMPLE 70

In an analogous manner to that described in Example 69, from t-butyl[(1S,2S,4S)-2-hydroxy-1-isobutyl-5-methyl-4-phenylhexyl] carbamate therewas obtained[4S,5S,7S]-4-(Boc-Phe-His-NH)-2,8-dimethyl-7-phenyl-5-nonanol in theform of a thick oil. MS: 648 (M+H)⁺.

The t-butyl [(1S,2S,4S)-2-hydroxy-1-isobutyl-5-methyl-4-phenylhexyl]carbamate used as the starting material was prepared as follows:

23 g of sodium in small portions were added at -35° within 90 minutes to1500 ml of liquid ammonia. After completion of the addition, 150 mg ofiron-(III) nitrate.9H₂ O were added. To this suspension were added,while stirring vigorously, 150 g (1 mol) of phenylacetic acid methylester in 500 ml of absolute tetrahydrofuran and, half an hour later, 100ml (1 mol) of isopropyl iodide were added dropwise. After completion ofthe addition, the ammonia was distilled off overnight. Water was addedslowly to the liquid residue and the mixture was extracted with ether.The organic extracts were washed with water, dried over sodium sulfateand evaporated under reduced pressure, to obtain 165.8 g (87%) of2-phenyl-3-methylbutyric acid methyl ester as a yellow oil which wasused directly in the next step.

A solution of 165.8 g (0.87 mol) of 2-phenyl-3-methylbutyric acid methylester, 52.0 q (1.30 mol) of sodium hydroxide, 1200 ml of methanol and600 ml of water was heated to reflux for one hour. After evaporation ofthe methanol under reduced pressure, dilution with water andacidification with conc. hydrochloric acid, the aqueous solution wasextracted with ether. The ethereal extracts were washed with water,dried over sodium sulfate and evaporated under reduced pressure, toobtain 146.3 g (95%) of 2-phenyl-3-methylbutyric acid in the form of ayellow oil which was used directly in the next step.

A solution of 146.3 g (0.82 mol) of rac. 2-phenyl-3-methylbutyric acidin 820 ml of acetonitrile was treated with 78.5 ml (0.615 mol) of(S)-(-)-α-phenylethylamine. The resulting crystals were filtered off andwashed with acetonitrile. After three-fold recrystallization fromacetonitrile, there were obtained 88.5 g of (+)-2-phenyl 3-methylbutyricacid as the α-phenylethylammonium salt, melting point 198°-200°, [α]_(D)²⁰ =+4.3° (c=1%, methanol). This salt was suspended in 1000 ml of ethylacetate and treated with 3N hydrochloric acid while cooling with ice.The ethyl acetate extracts were washed with water, dried over sodiumsulfate and evaporated under reduced pressure, to obtain 54.5 g of(S)-(+)-2-phenyl-3-methylbutyric acid as a light yellowish oil, [α]_(D)²⁰ =+61.3° (c=1%, chloroform).

A suspension of 19.5, g (0.51 mol) of lithium aluminium hydride in 750ml of absolute ether was heated to reflux. Within 4 hours there wasadded, dropwise, a solution of 54.5 g (0.307 mol) of (S)-(+)-2-phenyl3-methylbutyric acid in 250 ml of absolute ether. After heating toreflux for a further 2 hours, the suspension was treated carefully with1N hydrochloric acid and the ether phase was washed with water, dilutesodium bicarbonate solution, and once more with water. After drying theorganic phase over sodium sulfate and evaporation under reducedpressure, there were obtained 53.1 g of (S)-(+)-2-phenyl-3-methylbutanolas a thick oil which was used directly in the next step.

A solution of 49.3 g (0.3 mol) of (S)-(+) 2-phenyl-3-methylbutanol in400 ml of absolute methylene chloride was treated with 80 g (0.3 mol) oftriphenylphosphine. Thereafter, 53.4 g (0.3 mol) of N-bromosuccinimidewere added portionwise while stirring vigorously. After 16 hours, thereaction mixture was filtered and the filtrate was evaporated underreduced pressure. The residue was dissolved in hexane and purified bychromatography on silica gel, to obtain in this manner 34.9 g (51%) of(S)-(-)-2-phenyl-3-methylbromobutane as a volatile oil, [α]_(D) ²⁰=-19.6° (c=1%. chloroform).

A solution of 40.9 g (0.18 mol) of (S)-(-)-2-phenyl-3-methylbromobutanein 110 ml of tetrahydrofuran and 0.5 ml of 1,2-dibromoethane was slowlyadded dropwise to a suspension of 6.6 g of magnesium in 25 ml of ether.The temperature rose to 50°. Thereafter, the reaction mixture wasstirred at 50° for a further 2 hours and then cooled to -50°. Then, asolution of 13 g (0.06 mol) of N-t-butoxycarbonyl-L-leucinal in 40 ml oftetrahydrofuran was added slowly. After 16 hours at room temperature,the reaction mixture was treated with 200 ml of a 20% ammonium chloridesolution. The organic phase was dried over magnesium sulfate and thesolvent was evaporated under reduced pressure. The residue (24.3 g) waschromatographed on silica gel with a 4:1 mixture of hexane and ether, toobtain 9.3 g of t-butyl [(1S,2S,4S)-2-hydroxy-1-isobutyl-5-methyl-4-phenylhexyl]carbamate which has a melting point of 95°-96°after crystallization from hexane.

EXAMPLE 71

The following compounds were prepared in a manner analogous to thatdescribed in Example 1:

From 78 mg (0.20 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy4-isopropyl-5-hexenyl]imidazole-4-propionamide and 57 mg (0.24 mmol) ofethoxycarbonyl-L-phenyl-alanine, 57 mg of (2S,3S,5S)-1-cyclohexyl2-[(ethoxycarbonyl)-Phe-His-NH]-5-isopropyl 6-hepten-3-ol in the form ofa solid, MS: 610 (M+H)⁺ ;

From 78 mg (0.20 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 70.8 mg (0.25 mmol) of phenylacetyl-L-phenyl-alanine, 97 mg of(2S,3S,5S)-1-cyclohexyl-2-[(phenylacetyl)-Phe-His-NH]-5-isopropyl-6-hepten-3-olin the form of a solid, MS: 656 (M+H)⁺ ;

From 78 mg (0.20 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 68 mg (0.25 mmol) of 2-pyridylcarbonyl-L-phenylalanine, 88 mg of1-cyclohexyl-5-isopropyl 2 [(2-pyridylcarbonyl)-(Phe-His-NH]-6-hepten-3ol as a solid, MS: 643 (M+H)⁺ ;

From 78 mg (0.20 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 75 mg (0.25 mmol) of 2-phenylacetyl L-tyrosine, 110 mg of(2S,3S,5S)-1-cyclohexyl-5-isopropyl-2-[(phenylacetyl)-Tyr-His-NH]-6-hepten-3-olas a solid, MS: 672 (M+H)⁺ ;

From 78 mg (0.20 mmol) of(S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 72 mg (0.25 mmol) 2-pyridylcarbonyl L-tyrosine, 96 mg of(2S,3S,5S)-1-cyclohexyl-5-isopropyl-2-[(2-pyridylcarbonyl)-Tyr-His-NH]-6-hepten3-ol as a solid, MS: 659 (M+H)⁺ ;

From 175 mg (0.45 mmol) of(S)-α-amino-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 145 mg (0.5 mmol) of 2-pyridylcarbonyl-L-tyrosine, 150 mg of(S)-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-p-hydroxy-α-picolinamidohydrocinnamido]imidazole-4-propionamideas a solid. MS: 659 (M+H)⁺ ;

From 175 mg (0.45 mmol) of(S)-α-amino-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 150 mg (0.5 mmol) of phenylacetyl-L-tyrosine, 150 mg of(S)-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-p-hydroxy-α-(2-phenylacetamido)hydrocinnamamido]-imidazole-4-propionamideas a solid, MS: 672 (M+H)⁺ ;

From 175 mg (0.45 mmol) of(S)-α-amino-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 137 mg (0.5 mmol) of 2-pyridylcarbonyl-L-phenylalanine. 150 mg of(S)-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-picolinamidohydrocinnamamido]imidazole-4-propionamideas a solid, MS: 643 (M)⁺ ;

From 175 mg (0.45 mmol) of(S)-α-amino-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 141 mg (0.50 mmol) of phenylacetyl-L-phenylalanine, 150 mg of(S)-N-[(1S,2S,4R)-1-(cyclohexylmethyl)2-hydroxy-4-isopropyl-5-hexenyl]-α-[(S)-α-(2-phenylacetamido)hydrocinnamamido)imidazole-4-propionamideas a solid, MS: 656 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]-α-(3-phenyl-L-alanyl)imidazole-4-propionamide and 66 mg of1-(imidazolyl)-3-propionyl-D-proline, 126 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[(R)-1-[3-(1H-imidazol-1-yl)propionyl]-2-pyrrolidinecarboxamido]hydrocinnamamido]]imidazole-4-propionamideas a solid, MS: 757 (M+H)⁺ ;

From 111 mg (0.20 mmol) of (S)-α-[p-fluoro-L-alanyl)amino]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 47.8 mg (0.24 mmol) of 2-(2-pyridyl)benzoic acid. 120mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[2-(2-pyridyl)benzamido]-p-fluoro(hydcocinnamamido)]imidazole-4-propionamideas a solid, Ms: 737 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 75 mg (0.24 mmol) of Boc-D-Pro-Pro-OH, 122 mg of(2S,5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 832 (M+H)⁺.

From 269 mg (0.6 mmol) ofN-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 187 mg (0.6 mmol) of Boc-D-Pro-Pro-OH, 400 mg of t-butyl(R)-2-[[(S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinyl]carbonyl]-1-pyrrolidinecarboxylateas a solid, MS: 832 (M+H)⁺.

From 269 mg (0.5 mmol) ofN-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]α-(3-phenyl-L-alanyl)imidazole-4-propionamideand 260mg (0.6 mmol) of t-butoxycarbonyl D-phenylglycine, 110 mg oft-butyl[[(R)-α-[[(S)-α-[[(S)-1-[[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyI]benzyl]carbamateas a solid, MS 771(M+H)⁺.

From 269 mg (0.5 mmol) ofN-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 119 mg (0.6 mmol) of 2-(2-pyridyl)benzoic acid. 290 mg of(S)-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-[2-(2-pyridyl)benzamido]hydrocinnamamido]imidazole-4-propionamideas a solid, MS: 719 (M+H)⁺.

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 75 mg (0.24 mmol) of Boc-Pro-Pro-OH, 137 mg of(2S,3S,5S)-2-(Boc-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid. MS: 832 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 71 mg (0.24 mmol) of IVA-D-Pro-L-Pro-OH, 130 mg of(S)-N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[N-[1-[(1-isovaleryl-D-prolyl)-L-prolyl]-3-phenyl-L-alanyl]amino]imidazole-4-propionamideas a solid, MS: 816 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 67 mg (0.24 mmol) of N-t-butoxycarbonyl-N-methyl-L-phenylalanine,100 mg t-butyl[(S)-α-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]phenethyl]methylcarbamate as a solid, MS: 799 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 71 mg (0.24 mmol) of IVA-D-Pro-Pro-OH, 141 mg of(2S,3S,5S)-1-cyclohexyl-2-[(3-methylbutyryl)-D-Pro-Pro-Phe-His-NH]-5-isopropyl-6-hepten-3-olas a solid, MS: 816 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamide and 74 mg (0.24 mmol) of Boc-(Δ3-deshydro)-Pro-Pro-OH,125 mg of(2S,3S,5S)-2-[[[(S)-1-Boc-3-pyrrolin-2-yl]carbonyl]-Pro-Phe-His-NH]-1-cyclohexyl-5-isopropyl-6-hexen-3-olas a solid, MS: 830 (M+H)³⁰ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 75 mg (0.24 mmol) of Boc-Pro-D-Pro-OH- 135 mg of(2S,3S,5S)-2-(Boc-Pro-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 832 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 75 mg (0.24 mmol) of Boc-D-Pro-D-Pro-OH, 133 mg of(2S,3S,5S)-2-(Boc-D-Pro-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 832 (M+H)⁺ :

From 110 mg (0.20 mmol) of(S)-α-(Phe-methylamino)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideand 75 mg (0.24 mmol) of Boc-D-Pro-Pro-OH, 87 mg of(S)-α-[Boc-D-Pro-Pro-Phe-N(CH₃)]N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideas a solid, MS: 846 (M+H)⁺ ;

From 107 mg (0.20 mmol) of N-[(1S,2S,4S)-1-(cyclohexylmethyl)2-hydroxy-4 isopropyl5-hexenyl]-α-(3-phenyl-L-alanyl)imidazole-4-propionamide and 55 mg (0.24mmol) of (S)-N-t-butoxycarbonyl-piperidine-2-carboxylic acid, 127 mg of(2S,3S,5S)-1-[[[(S)-1-Boc-2-piperidinyl]carbonyl]-Phe-His-NH]-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, Ms: 749 (M+H)⁺ ;

From 54 mg (0.10 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 49 mg (0.12 mmol) of Boc-D-Pro-D-Pro-Pro-OH, 57 mg of(2S,3S,5S)-2-(Boc-D-Pro-D-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 927 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 56 mg (0.24 mmol) of(R)-N-t-butoxycarbonyl-thiazolidine-2-carboxylic acid, 126 mg of(2S,3S,5S)-2-[[[(R)-3-Boc-4-thiazolidinyl]carbonyl-Phe-His-NH]-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 753 (M+H)⁺ ;

From 80 mg (0.123 mmol) of(2S,3S,5S)-1-[[[(S)-2-piperidinyl]carbonyl]-Phe-His-NH]-1-cyclohexyl-5-isopropyl-6-hepten-3-oland 64 mg (0.30 mmol) of Boc-D-Pro-OH, 106 mg of(2S,3S,5S)-2-(Boc-D-Pro-Pip-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 846 (M⁺);

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 79 mg (0.24 mmol) of(R)-N-t-butoxycarbonyl-thiazolidinyl-1-carbonyl-proline. 163 mg of(2S,3S,5S)-2-[[[(R)-3-Boc-4-thiazolidinyl]carbonyl]-Pro-Phe-His-NH]-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 850 (M+H)⁺ ;

From 107 mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 71 mg (0.24 mmol) of 2-(2-pyridyl)benzoic acid, 140 mg of(2S,3S,5S)-1-cyclohexyl-5-isopropyl-2-[[2-(2-pyridyl)benzoyl]-Pro-Phe-His-NH]-6-hepten-3-ol in the form of thedihydrochloride. MS: 816 (M+H)⁺ ;

From 107 mg (0.20 mmol) of(N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 57 mg (0.24 mmol) of3-dimethyl-3-(1-imidazolyl)propionyl-Pro-Pro-OH, 160 mg of(2S,3S,5S)-1-cyclohexyl-2[(3,3-dimethyl-3-imidazol-1-ylpropionyl)-Pro-Pro-Phe-His-NH]-5-isopropyl-6-hepten-3-olas a solid. MS: 882 (M+H)⁺ ;

From 107 mg (0.20 mmol) of(N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 77 mg (0.24 mmol) of N-(1-imidazolyl)acetyl-D-Pro-Pro-OH, 160 mg of(2S,3S,5S)-1-cyclohexyl-2-[(imidazol-1-ylacetyl)-D-Pro-Pro-Phe-His-NH]-5-isopropyl-6-hepten-3-olin the form of the dihydrochloride as a solid. MS: 840 (M+H)⁺ ;

From 107 mg (0.20 mmol) of(N-[(1S,2S,4R)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 77 mg (0.24 mmol) of N-(1-imidazolyl)acetyl-D-Pro-Pro-OH, 148 mg of(2S,3S,5R)-1-cyclohexyl-2-[(imidazol-1-ylacetyl)D-Pro-Pro-Phe-His-NH]-5-isopropyl-6-hepten-3-ol in the form of thedihydrochloride, as a solid, MS: 840 (M+H)⁺ ;

From 107 mg (0.20 mmol) of(N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl5-hexenyl]-α-(3-phenyl-L-alanyl)imidazole-4-propionamide and 83 mg (0.24mmol) of benzyloxycarbonyl-Fro-pro-OH, 155 mg of (2S,3S5S)-2-(benzyloxycarbonyl-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olas a solid, MS: 866 (M+H)⁺ :

The(S)-α-(Phe-methylamino)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideused as the starting material was prepared as follows:

A mixture of 1.50 g (4 mmol) ofN-α-N-im-di-t-butoxycarbonyl-N-α-methylhistidine, 1.0 g (3.4 mmol) of(S,S,S)-6-amino-6-cyclohexylmethyl-4-isopropyl-1-hexen-5-olhydrochloride, 1.33 g (3.5 mmol) of HBTU, 7.8 ml of N-methylmorpholineand 20 ml of dimethylformamide was stirred at room temperature for 4hours. The solvent was evaporated under reduced pressure and the oilyresidue was dissolved in ether. The organic phase was washed firstlywith a sodium bicarbonate solution and thereafter with saturated sodiumchloride solution and, after drying over sodium sulfate, was evaporatedunder reduced pressure, to obtain 2.1 g of(S)-3-(t-butoxycarbonyl)-α-[1-(t-butoxycarbonyl)-N-methyl-formamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidewhich was used directly in the next step.

2.1 g of(S)-3-(t-butoxycarbonyl)-α-[1-(t-butoxycarbonyl)-N-methylformamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidewere dissolved in 30 ml of 3N hydrogen chloride in dioxan and themixture was left to stand at room temperature for 5 hours. 500 ml ofether were added and the precipitate formed was filtered off. Theprecipitate was washed with ether and dissolved in water. Solid sodiumbicarbonate was added to the aqueous solution and the mixture wasextracted several times with ethyl acetate, to obtain there was obtained0.85 g of(S)-α-(N-methylformamido)-N-[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl)imidazole-4-propion-amidewhich was used directly in the next step.

A mixture of 0.85 g (2.1 mmol) of(S)-α-(N-methylformamido)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,0.67 g (2.5 mmol) of N-t-butoxycarbonylphenylalanine, 0.84 g (2.2 mmol)of HBTU. 0.3 ml of N-methylmorpholine and 20 ml of dimethylformamide wasto stand at room temperature for 60 hours and poured into a saturatedsodium bicarbonate solution. The precipitate thus formed was filteredoff and dissolved in ethyl acetate. The organic solution was dried overmagnesium sulfate and evaporated under reduced pressure. The residueremaining was triturated with hexane and filtered off, to obtain 1.35 gof(S)-α-(Boc-Phe-methylamino)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidein the form of a powder which was used directly in the next step.

1.3 g of(S)-α-(Boc-Phe-methylamino)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamidewere dissolved in 30 ml of 3N hydrogen chloride in dioxan and themixture was left to stand at room temperature for 1 hour. Thereafter,200 ml of ether were added and the mixture was stirred at roomtemperature for 16 hours. The precipitate formed was filtered off,washed with ether and dissolved in water. Solid sodium bicarbonate wasadded to the aqueous solution and the mixture was then extracted severaltimes with ethyl acetate, to obtain 0.97 g of(S)-α-(Phe-methylamino)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidewhich was used directly in the next step.

The(2S,3S,5S)-1-[[[(S)-2-piperidinyl]carbonyl]Phe-His-NH]-1-cyclohexyl-5-isopropyl-6-hepten-3-olwhich was also used as a starting material was prepared by cleaving offthe t-butoxycarbonyl group from(2S,3S,5S)-1-[[[(S)-1-Boc-2-piperidinyl]carbonyl-Phe-His-NH]-l-cyclohexyl-5-isopropyl-6-hepten-3-olby means of hydrochloric acid in dioxane and was used directly in thenext step.

Example 72

A mixture of 31 mg (0.21 mmol) of N-cyano-dimethyldithiocarbamate, 107mg (0.20 mmol) ofN-[(1S,2S,4S)-1-(cyclohexylmethyl]-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-(3-phenyl-L-alanyl)imidazole-4-propionamideand 1 ml of methanol was allowed to stand at room temperature for 24hours. The solvent was evaporated under reduced pressure and the residuewas digested with a 1:1 mixture of hexane and ether, to obtain 112 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[N-[(cyanoimino)(methylthio)methyl]-3-phenyl-L-alanyl]amino]imidazole-4-propionamide asa solid, MS: 636 (M+H)⁺.

Example 73

100 mg of(2S,5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-olwere dissolved in 3 ml of 3.2N hydrogen chloride in dioxane, thesolution was allowed to stand for 1 hour and the desired product wasprecipitated by the addition of ether. The precipitate was filtered offand dried under reduced pressure, to obtain 100 mg of[2S,3S,5S]-1-cyclohexyl-2-(D-Pro-Pro-Phe-His-NH)-5-isopropyl-6-hepten-3-olin the form of the dihydrochloride as a solid MS: 732 (M+H)⁺.

EXAMPLE 74

41 mg (0.05 mmol) of(2S,3S,5S)-1-cyclohexyl-2-[(3-methylbutyryl)-D-Pro-Pro-Phe-His-NH]-5-isopropyl-6-hepten-3-olwere dissolved in 5 ml of methanol and hydrogenated in the presence of20 mg of palladium-on-carbon (5%). After completion of the hydrogenuptake, the catalyst was filtered off and the solvent was evaporatedunder reduced pressure. Trituration of the residue with hexane anddrying yielded 34 mg of(2S,3S,5S)-1-cyclohexyl-5-isopropyl-2-(isovaleryl-D-Pro-Pro-Phe-His-NH)-3-heptanolas a solid, MS: 818 (M+H)⁺.

The above hydrogenation can also used to produce the correspondingisomeric compound when carried out under the following conditions:

200 mg of starting material in 15 ml of methanol were hydrogenated inthe presence of 50 mg of palladium-on-carbon (5%) and thereafter themixture was worked-up as usual, to obtain 184 mg of(2S,3S,5R)-1-cyclohexyl-5-isopropyl-2-(isovaleryl-D-Pro-Pro-Phe-His-NH)-3-heptanolas a solid, MS: 818 (M+H)⁺.

Example 75

80 mg (0.25 mmol) of 3-(1-imidazolyl)propionyl-Pro-Pro-OH, 110 mg (0.20mmol) of(S)-α-(Phe-methylamino)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide,84 mg (0.22 mmol) of HBTU, 0.03 ml of N-methylmorpholine and 2 ml ofdimethylformamide was left to stand at room temperature for 16 hours.The reaction mixture was poured into 50 ml of a 5% sodium carbonatesolution and the milky suspension was extracted several times with ethylacetate. The organic extracts were dried over magnesium sulfate andevaporated under reduced pressure. The residue was dissolved in 10 ml ofethyl acetate and the solution was treated with 1.5 ml of a 3.0Nsolution of hydrogen chloride in dioxane. The precipitate thus formedwas filtered off and dried, to obtain 143 mg of (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[[3-(imidazol-1-yl)propionyl]-D-Pro-Pro-Phe-N-(methyl)]imidazole-4-propionamidehydrochloride as a solid, MS: 868 (M+H)⁺.

In a manner analogous to that described above, from 77 mg (0.24 mmol) of2-(1-imidazolyl)acetyl-Pro-Pro-OH and 110 mg of(S)-α-(Phe-methylamino)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamidethere were manufactured 155 mg of(S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(imidazol-1-ylethyl)D-Pro-Pro-Phe-N-(methyl)]imidazole-4-propionamide dihydrochloride as asolid. MS: 840 (M+H)⁺.

Example 76

105 mg of(S)-N-((1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[[3-(imidazol-1-yl)propionyl]-D-Pro-Pro-Phe-N-(methyl)]imidazole-4-propionamidehydrochloride were dissolved in 15 ml of methanol and hydrogenated inthe presence of 50 mg of palladium-on-carbon. After completion of thehydrogen uptake, the catalyst was filtered off and the filtrate wasevaporated to dryness. The residue was triturated with ether andfiltered off to obtain 65 mg of(2S,3S,5S)-1-cyclohexyl-2-[(3-imidazol-1-ylpropionyl)-D-Pro-Pro-Phe-His-NH]-5-isopropyl-3-heptanoldihydrochloride as a solid. MS: 856 (M+H)⁺.

Example 77

A sterile filtered aqueous solution of(S)-α-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideis mixed while warming with a sterile gelatine solution, which containsphenol as a preserving agent, under aseptic conditions so that 1.0 ml ofsolution has the following composition:

    ______________________________________                                        (S)-α-[(R)-2-Benzyl-5,5-dimethyl-4-oxohexan-                                                       3.0    mg                                          amido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-                                  hydroxy-4-isopropyl-5-hexenyl]imidazole-4-                                    propionamide                                                                  Gelatine                   150.0  mg                                          Phenol                     4.7    mg                                          Distilled water to         1.0    ml                                          ______________________________________                                    

The mixture is filled into vials of 1.0 ml under aseptic conditions.

Example 78

5 mg of(S)-α-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamideare dissolved in 1 ml of an aqueous solution with 20 mg of mannitol. Thesolution is filtered sterile and filled under aseptic conditions into a2 ml ampoule, cooled to a low temperature and lyophilized. Prior toadministration, the lyophilizate is dissolved in 1 ml of distilled wateror 1 ml of physiological saline. The solution is used intramuscularly orintravenously. This formulation can also be filled into double chamberinjection ampoules.

Example 79

500 mg of finely milled (5.0 μm) of(S)-α-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamideare suspended in a mixture of 3.5 ml of Myglyol 812 and 0.08 g of benzylalcohol. This suspension is filled into a container having a dosagevalve. 5.0 g of Freon 12 are filled into the container through the valveunder pressure. The Freon is dissolved in the Myglyol-benzyl alcoholmixture by shaking. This spray container contains about 100 individualdosages which can be applied individually.

We claim:
 1. A compound of the formula ##STR12## in which R¹ is hydrogenor methyl, R² is imidazol-4-yl, R³ is isobutyl, cyclohexylmethyl, orbenzyl, R⁴ is phenyl, furyl, vinyl, ethyl, or 1,2-dihydroxyethyl and Ais -Y-Z in which Y is a bivalent residue of optionally N- and/orα-methylated phenylglycine, cyclohexylglycine, phenylalanine,cyclohexylalanine, 4-fluorophenylalanine, 4-chlorophenyldamine,tyrosine, methionine, proline, α-napththylalanine, homophenylalanine,aspartic acid ethyl ester, or glutamic acid benzyl ester linked with Zat the N-terminal, and Z is hydrogen, a group of the formula ##STR13##or is the residue, linked with Y at the C-terminal, of optionally N-and/or α-methylated natural amino acid with the L-configuration which isoptionally N-substituted with the group R^(b) --CO-- or R^(a) --O--CO--or of an epimer of such an amino acid with the D-configuration or of adipeptide from two such amino acids or a tripeptide from three suchamino acids or the group R^(b) --CO-- or R^(a) --O--CO--, wherein R^(a)is an optionally substituted residue selected from C₁₋₁₈ alkyl; C₂₋₈alkenyl; C₂₋₈ alkynyl; C₃₋₈ cycloalkyl; C₃₋₈ cycloalkenyl; C₅₋₁₀bicycloalkyl; C₈ tricycloalkyl; C₅₋₁₀ bicycloalkenyl; C₃₋₈cycloalkyl-C₃₋₈ alkyl; C₃₋₈ cycloalkenyl-C₁₋₈ alkyl; C₃₋₈cycloalkyl-C₂₋₈ alkenyl; C₃₋₈ cycloalkenyl-C₂₋₈ alkenyl; aryl selectedfrom phenyl, naphthyl, and fluorenyl; a heteroaromatic residue, aheteroaromatic-C₁₋₈ alkyl residue, an aryl C₁₋₈ alkyl residue, or aheterocycle, wherein the heteroaromatic portion of the heteroaromaticand heteroaromatic-C₁₋₈ -alkyl residues is selected from the group ofmoieties consisting of pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyramidinyl, indolyl, quinolyl,isoquinolyl, quinoxalinyl and β-carbolinyl, or a benz-fused derivativeof the above moieties, said above moieties which contain a nitrogen atomcan be substituted at said nitrogen atom with alkyl, phenyl orphenylalkyl, said above moieties also can be substituted on at least oneof the carbon atoms with alkyl, phenyl, phenylalkyl, halogen, hydroxy,alkoxy, phenylalkoxy, and oxo, the aryl portion of the aryl-C₁₋₈ -alkylresidue is selected from the group consisting of phenyl, α- orβ-naphthyl, indenyl and phenanthryl which can be substituted with atleast one of alkyl, alkoxy, alkanoyloxy, amino, alkylamino,dialkylamino, alkanoylamino hydroxy, halogen trifluoromethyl and nitro,the heterocycle is selected from the group consisting ofpyrrolidin-3-yl, 4-hydroxypyrrolidin-2-yl, 5-oxo-pyrrolidin-2-yl,piperidin-2yl, piperdin-3-yl, 1-methylpiperidin-2-yl,1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, morpholin-2yl,morpholin-3yl, thiomorpholin-2yl, thiomorpholin-3yl,1,4-dimethylpiperazin-2-yl, 2-indolinyl, 3-indolinyl,1,2,3,4-tetrahydroquinol-2-, -3 or -4-yl,1,2,3,4-tetrahydroisoquinol-1-, -3- or -4-yl,1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl, tertiary butoxy-carbonylpiperidin-2-yl, thiazolidin-4-yl,hexahydro-8a-methyl-5-oxo-5H-thiazolo[3,2-a]pyrid-3-yl, andtetrahydro-7a-methyl-pyrrolo[2,1-b]thiazol-3-yl; and R^(b) is R^(a) orhydrogen, the compound being in the form of an optionally purediastereomer, diastereomeric mixture, diastereomeric racemate of mixtureof diastereomeric racemates; or a pharmaceutically acceptable usablesalt of the compound.
 2. The compound of claim 1 wherein Z is theresidue, linked with Y at the C-terminal of the L-configuration or itsepimer of optionally substituted proline, prolylproline, histidine,methionine, N-methylphenylalanine, histindinylproline,prolylprolylproline, the amino group in each case is optionallysubstituted with t-butoxycarbonyl, benzoxycarbonyl, isovaleryl or thegroup R^(b) --CO--.
 3. The compound of claim 2 wherein Z is Boc-D-Pro,D-Pro, 5-oxo-Pro, 4imidazolylproprionyl-Pro,3-hydroxy-2-pyridylcarbonyl-Pro, dibenzylacetyl-Pro,isoalenylcarbonyl-Pro, Boc-Pro, Pro, t-butylcarbonyl-Pro,t-butylcarbonyl-Met, Boc-His, Boc-His(3Bom),1-imidazolylproprioyl-D-Pro, Boc-D-Pro-Pro, Boc-Pro-Pro,isolalenyl-D-Pro-L-Pro, Boc-Pro-D-Pro, Boc-D-Pro-D-Pro,Boc-D-Pro-D-Pro-Pro, Boc-thiazolidin-4-ylcarbonyl-Pro,2-(2-pyridyl)benzoyl-Pro,2-(1-imidazolyl)-2,2-dimethylpropionyl-Pro-Pro,1-imidazolylacetyl-D-Pro-Pro, benzyloxycarbonyl-Pro-Pro, D-Pro-Pro,1-imidozolylpropioyl-D-Pro-Pro, or Boc-3-pyrrolin-2-yl-Pro.
 4. Thecompound of claim 1 wherein Z is Boc, 3,3-dimethylbutyryl, isovaleryl,cyclopentylcarbonyl, Boc-aminovaleryl, aminoethylglycyl,3-(4-hydroxyphenyl)propionyl, 3-pyridylcarbonyl, 4-pyridyloxylcarbonyl,3-pyridyloxylcarbonyl, 4-imidazolylzylcarbonyl,1,3,4,5-cyclohexyl-carbonyl, 2-quinolylcarbonyl,methylcarbonylethylcarbonyl, 3-pyridylmethylcarbonyl,4-chlorophenylvinylcarbonyl, 4-nitrophenylvinylcarbonyl,ethoxycarbonylvinylcarbonyl, diphenylaminocarbonyl, isobutoxycarbonyl,Boc-aminoisobutyryl, fluorenylmethylcarbonyl-2-t-butoxyalkyl,fluorenylmethoxycarbonyl, adamatylmethylcarbonyl, phenoxycarbonyl,2,2,2-trichloroethoxy, Boc-aminocyclohexycarbonyl, 2-t-butyoxyalanyl,aminovaleryl, ethoxycarbonylethoxycarbonly, adamatylacetyl,3-pyrridylacetyl, fluorenylacetyl, ethoxycarbonyl,4-aminophenypropionyl, acetylpropionyl, 4-hydroxyphenylpropionyl,3-pyridiylpropionyl, 4-imidozalylpropionyl, Boc-aminoisobutyl,1-amino-2-hydroxyproprioyl, dibenzyaminoacarbonyl, morpholinecarbonyl,4-biphenyloxyethylaminocarbonyl, N-Boc-2-azetidinecarbonyl,hexahydro-8a-methyl-5-oxo-5H-thiazole[3,2-a]pyridyl-3-carbonyl,tetrahydro-7a-methylpyrrolo[2,1-b]thiazolyl-3-carbonyl,Boc-aminovalerylaminoproprionyl, phentylacetyl, 2-pyridylcarbonyl,2-(2-pyridyl)benzoyl, Boc-phenylalycyl, boc-2-piperidinylcarbonyl, orBoc-thiazolidin-4-ylcarbonyl.
 5. A compound in accordance with claim 2,wherein Y is phenylalanine and Z is the residue, linked with Y at theC-terminal, of a N- and/or α-methylated natural amino acid with theL-configuration which is optionally N-substituted with the group R^(b)--CO-- or R^(a) --O--CO-- or of an epimer of such an amino acid with theD-configuration or of a dipeptide from two such amino acids or the groupR^(b) --CO-- or R^(a) --O--CO--, wherein R⁴ is an optionallysubstituted, saturated or unsaturated aliphatic, cycloaliphatic,cycloaliphatic-aliphatic hydrocarbon residue having from 1 to 18 carbonatoms, an optionally substututed aromatic, heteroaromatic,aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon residuehaving from 1 to 18 carbon atoms or an optionally substituted, saturated5- or 6-membered heterocycle and R^(b) is hydrogen or has the samemeaning as R^(a) the residue, linked with Y at the C-terminal, ofproline, prolyproline or histidinylproline, whereby the amino group ineach case is substituted t-butoxy-carbonyl, benzoxycarbonyl, isovalerylor the group R^(b) --CO-- in which R^(b) is a heteroaromatic-aliphatichydrocarbon residue having from 1 to 10 carbon atoms or a saturated 5-or 6-membered heterocycle.
 6. A compound in accordance with claim 1which ist-butyl(R)-2-[[(S)-α-]](S)-1-[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropylhexyl]-2-imidazol-4-ylethyl]carbamoyl]phenethy]carbamoyl]-1-pyrrolidinecarboxylate.7. A compound in accordance with claim 2 which is(2S,3S,5S)-2-(Boc-D-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol8. A compound in accordance with claim 1 which is(2S,5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-1-cyclohexyl-5-isopropyl-6-hepten-3-ol.9. A compound in accordance with claim 1 which isN-(S)-[(1S,2S,4S)-1-(Cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]-.alpha.-[(S)-α-3-methylbutyramido]imidazole-4-propionamide.10. A compound in accordance with claim 1 which is t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate.11. A compound in accordance with claim 1 which is t-butyl[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-cyclohexylmethyl-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate.